Open access peer-reviewed chapter

Flavonoid-Mediated Modulation of CYP3A Enzyme and P-Glycoprotein Transporter: Potential Effects on Bioavailability and Disposition of Tyrosine Kinase Inhibitors

Written By

Muzaffar Iqbal

Submitted: 21 October 2018 Reviewed: 04 May 2020 Published: 05 June 2020

DOI: 10.5772/intechopen.92712

From the Edited Volume

Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health

Edited by Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu

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The consumption of herbal products and dietary supplements along with conventional medicines has raised concerns regarding herb-drug interactions. The available literature from experimental and clinical studies suggested that the consumption of herbs or dietary supplements that modulate efflux proteins, especially P-glycoprotein (P-gp) and metabolic enzyme CYP3A, may cause clinically relevant herb-drug interactions by alteration of bioavailability and disposition profiles of targeted drug. It has been also hypothesized that both CYP3A and P-gp work synergistically to limit systemic exposure of orally administered substrate drugs. Many in vitro and in vivo studies suggested that co-administration of flavonoids significantly enhances the bioavailability of orally administered drugs, which may be due to inhibition of the CYP3A enzyme and P-gp transporter. Recently, a large number of orally administered tyrosine kinase inhibitors (TKIs) have been clinically approved for cancer chemotherapy, and many are currently estimated to be under development. TKIs are all primarily metabolized by CYP3A, and most of them are also substrates of P-gp. Numerous studies have suggested that the plasma exposure of orally administered TKIs increases when co-administered with other drugs due to their dual inhibitory activities against P-gp and CYP3A. However, limited data are available regarding the interaction between flavonoids and TKIs. The objective of this article is to review the potential role of flavonoids in modulation of CYP3A enzyme and P-gp transporter and their influence on bioavailability and disposition of TKIs.


  • flavonoids
  • tyrosine kinase inhibitors
  • CYP3A4
  • P-glycoprotein
  • bioavailability
  • disposition

1. Introduction

Due to common belief that natural medicines are much safer than synthetic one, the use of complementary and alternative medical therapies (CAMs) has become a common trend around the world. It can be used either alone or in combination with prescription medicines [1]. According to an estimate of World Health Organization (WHO), approximately 80% of the developing countries’ population relies on CAMs for their primary healthcare needs [2, 3]. CAMs have been also become popular around the developed countries, and this has led to a tremendous growth in international herbal drug market for the last 15 years [4, 5, 6]. Consumption of CAMs is more pronounced in patients diagnosed with cancer or human immune virus (HIV) infection, especially with regard to various antidepressant and energy treatments to cope with their mental and physiological instability [7]. The bioavailability and the distribution characteristics are the key factor for the therapeutic effects of pharmaceuticals at their site(s) of action in the tissue [8]. Due to higher consumption of CAMs (herbal extracts and dietary supplements) with prescription medicines, there is a growing awareness that herbal remedies and/or phytoconstituents may affect the bioavailability and disposition characteristics of conventional pharmaceuticals [9]. The medical and scientific literature supported by in vitro and in vivo laboratory studies including preclinical and clinical trials suggested that the co-administration of natural products or its phytoconstituents may affect the metabolism and bioavailability of prescription drugs, which significantly increasing the risk of serious (clinical) adverse reactions or therapeutic failure. The primary mechanisms underlying the herb-drug interactions involve either the induction or the inhibition of intestinal drug efflux pumps (including efflux proteins, such as P-gp and MRPs) and the intestinal and hepatic metabolism mediated by cytochrome P450 enzymes (CYP3A) [10, 11, 12]. Hence, the consumption of herbs that can modulate efflux proteins and/or CYP3A may cause clinically relevant herb-drug interactions and alter drug bioavailability [13, 14]. Any inhibitory effect of herbal extracts/constituents on efflux proteins and/or CYP3A may result in high exposure of substrate drugs in plasma and tissue and lead to toxicity, whereas any inductive effect may cause low exposure, leading to a decrease in efficacy and treatment failure.

The biological effects produced by CAMs are due to the presence of various classes of phytochemicals present there, that is, alkaloids, flavonoids, terpenoids, carotenoids, polyketides, and phenylpropanoids. Among them, flavonoids have attracted much interest due to their numerous pharmacological activities and health benefit in the form of their antioxidant, anti-inflammatory, antimutagenic, antibacterial, antiangiogenic and enzyme modulatory, antiallergic, and anticancer activities [15, 16] and become the main components of herbal products where it presents in the form of quercetin, genistein, hypericin, kaempferol, and silibinin. There is accumulated evidence in the literature, which confirms that flavonoids modulate drug metabolism. Modulation may happen by either (1) altering the expression and/or activity of P450 enzymes, (2) affecting the P-gp-mediated cellular efflux of drugs, and/or (3) inhibiting the intestinal glucuronidation of the drug. This evidence confirms that the consumption of flavonoids or flavonoid-containing dietary supplements with conventional pharmacotherapeutic regimens should need to be examined to avoid drug-flavonoid interactions [17, 18, 19, 20, 21].

Among the novel classes of anticancer drug development, small molecule tyrosine kinase inhibitors (TKIs) currently represent one of the most promising and rapidly expanding groups. Almost 25 TKIs (mostly in oral dosage form) have been already approved by international drug agencies, >130 are being evaluated in different phases of clinical trials, and many more are in various stages of development [22, 23]. Most of TKIs are primarily metabolized by CYP3A4 and also interact with P-gp and/or Breast Cancer Resistance Protein (BCRP) where it serves as both substrates and inhibitors. Considering the dual roles of TKIs on both CYP3A4 and drug transporters (P-gp, BCRP) and its influence in drug disposition, the potential of TKI-drug interactions is an important consideration [24, 25]. In addition, most TKIs are being used orally and prescribed for long duration along with other medications, which may result in significant drug-drug interactions (DDI). This review provides a comprehensive overview of the potential role of flavonoids in modulation of CYP3A enzyme and P-gp transporter and their possible influence on bioavailability and disposition of tyrosine kinase inhibitors (Figure 1).

Figure 1.

Schematic layout for prediction of flavonoids in modulation of CYP3A enzyme and P-gp transporter and its influence on disposition of TKIs.


2. CYP3A

Cytochrome P450 enzymes (CYP) are the most versatile enzyme system involved in detoxification and oxidative metabolism of various endogenous substrates (steroid hormones, lipids, and bile acids) and xenobiotics (drugs, environmental pollutants, and dietary products) [26, 27]. It consists of over 400 isoforms, and their activities can be increased or decreased by many drugs either by inducing the biosynthesis or by directly inhibiting its activity, which is a major source for drug-induced toxicity via DDI. CYP3A enzymes, which constitute the predominant phase I drug-metabolizing enzymes, are estimated to metabolize between 50 and 70% of currently administered drugs [28]. Alone CYP3A4, which is the most abundant congener of the CYP3A family contributes approximately 30% of hepatic CYP activity and more than 70% of intestinal CYP activity [29]. Many drugs used in different types of therapies are substrates for CYP3A4, and it is presented at high levels in both liver and intestine [30, 31]. Reports from in vitro and in vivo studies have already established that naturally occurring dietary supplements and phytoconstituents can modulate hepatic and enterocytic CYP activity.

CYP inhibition-mediated DDI is widely recognized, and the necessity of the enzyme inhibition studies is included in the guidance from the USFDA [32]. Usually, two types of CYP inhibition occur: (1) reversible inhibition represented by competitive inhibition, which is concentration-dependent inhibition and (2) irreversible inhibition, also called mechanism-based inhibition (MBI), where during inhibition process enzyme is inactivated by stable complex formation with a metabolite. In MBI, enzyme reduction activity continues until the inactivated CYP is replaced by a newly synthesized CYP, the duration of the elevated blood concentration of a drug coadministered with a mechanism-based inhibitor is longer. Therefore, MBI requires more attention because they have been reported to cause unanticipated adverse effects [33, 34].


3. P-gp

P-gp is an adenosine triphosphatase (ATPase) energy-dependent, membrane-bound protein that belongs to the ABC efflux transporter family [35]. The ABCB1 gene, which is also known as the multidrug resistance 1 (MDR1), encodes P-gp and is responsible for cellular efflux of numerous drugs [36]. It is more prominent in various resistant human tumors, where it is believed to be the major factors responsible for multidrug resistant (MDR). P-gp-mediated transport of drugs is saturable, ATP-dependent, osmotically sensitive mechanism that generates a concentration gradient. In intestines, P-gp expressed in apical side of the epithelial cells where it pumps the drug back into the GI lumen resulting in fecal excretion. In liver, it presents in canalicular surface of hepatocytes to remove drug and metabolites from the interior of the cell. In brain, it is expressed in endothelial cells of blood brain barrier and prevented the entry of xenobiotics into brain. In kidney, it is expressed in proximal tubes of kidney to efflux drug into urine and in certain hematological cells to put drug back into circulation [37, 38, 39, 40]. Higher expression of P-gp in excretory organs (liver and kidney) facilitates metabolism of substrate drugs via biliary excretion and renal elimination. As an efflux transporter, ABCB1 prevents intestinal absorption of orally administered drugs and limits its oral bioavailability. A broad range of clinically used drugs are substrate of P-gp, including anticancer agents (anthracyclines, vinca alkaloids, epipodophyllotoxins, methotrexate, and taxol) [41], cardiac drugs (digoxin and quinidine) [42], protease inhibitors (saquinavir, indinavir, and ritonavir) [43], immunosuppressants (cyclosporine) [44], and antibiotics (actinomycin D) [45].


4. Interplay between CYP3A and P-gp

Various preclinical and clinical studies have postulated that both CYP3A enzyme and P-gp transporter display strong effects in modulation of oral drug bioavailability and elimination of numerous drugs. Both CYP3A and P-gp act in functional collaboration during the first-pass elimination of drug [46]. Extensive overlap exists between the substrate specificities and the tissue-specific expression patterns of P-gp and CYP3A, especially in the liver (hepatocytes) and intestine (enterocytes) [47, 48]. It has also been predicted that the orally administered drugs, which are dual substrates of P-gp and CYP3A, the back-transportation mechanism by P-gp in intestinal epithelial cells, are available for further CYP3A4-mediated metabolism within these cells resulting in massive first-pass effects in intestine [49]. The combined action of these two pathways was expected to be more efficient than the sum of their individual activities, resulting in synergistic effects of P-gp and CYP3A.

Two mechanistic frameworks have been suggested to support the possible synergistic action of P-gp and CYP3A in intestine. Under the first mechanism, P-gp acts to decrease the level of intracellular concentration of a substrate drug in enterocytes, thus preventing possible saturation of the CYP3A enzyme by maintaining the drug within the linear range for metabolic activity. Under the second mechanism, the functional effects of P-gp, together with subsequent drug reuptake, allow the repetition of drug substrate, and therefore, probability of the drug to be metabolized increases by prolonged access to enterocyte CYP3A. The above cyclic repetition of drugs per se would itself increase the drug metabolism, even without considering saturating or nonsaturating conditions for CYP3A [50]. Based on above evidence, it is concluded that induction and inhibition of (intestinal) P-gp and CYP3A4 are important mechanisms underlying DDIs [51].

The hypothesis of synergistic collaboration between CYP3A and P-gp was clarified in a study that showed a dramatic increase in the systemic exposure of docetaxel and the risk of intestinal toxicity in P-gp−/−CYP3A−/− double knockout mice. After oral administration of docetaxel, 3-fold and 12-fold increases in bioavailability were observed in P-gp−/− and CYP3A−/− mice, respectively, in comparison with wild-type mice. However, when both of the primary detoxification systems were missing, that is, in P-gp−/−CYP3A−/− double knockout mice, bioavailability showed a disproportionate increase in >70-fold in comparison with wild-type mice [48].

Within the context described above, it is clear that drugs that are dual substrates for P-gp and CYP3A are highly susceptible to herb-drug interactions. Therefore, the consumption of herbs that modulate efflux transporters and CYP3A may cause clinically significant drug-herb interactions and alter drug bioavailability [13, 14]. The inhibitory effect of herbs on P-gp and CYP3A may result in increasing the drug concentration level in the plasma and tissues, leading to toxicity, whereas any inductive effect may result in lowering the concentration level, leading to loss of efficacy and/or treatment failure (Figure 2).

Figure 2.

Potential functional relationships between P-gp and CYP3A4 in enterocytes.


5. Regulation of CYP3A and P-gp expression

Pregnane X receptor (PXR) is a highly promiscuous nuclear hormone receptor, generally expressed on sites that are important to drug dispositions (e.g., small intestine, liver, and kidney). The human orthologue of PXR is also known as steroid and xenobiotics receptor (SXR) and is coded by NR 112. It has been reported that PXR regulates the expression of CYP3A and several other genes encoding protein and other enzymes, which involves in drug disposition including P-gp [52, 53]. Based on this evidence, Maglich et al. hypothesized that PXR plays a more important role in the regulation of drug metabolizing enzymes and drug transporters in the small intestines [54]. The observation that PXR regulates both CYP3A and P-gp provides further evidence for the argument that these proteins coordinately mediate detoxification of many xenobiotics during oral absorptions [46]. Synold et al. were the first to describe coregulation of drug metabolism and efflux via CYP3A and P-gp in liver and intestine by the human receptor PXR/SXR. Their results indicate that paclitaxel reduces its own oral bioavailability by activating the PXR and induces its own metabolism and biliary elimination [55].


6. Experimental models for P-gp and CYP3A-mediated DDI studies

6.1 In vitro model for CYP3A and P-gp studies

The in vitro CYP inhibition study is usually performed in human liver microsomes (HLMs) or human liver hepatocytes (HLHs), Caco-2 cell lines, or recombinant CYP (rCYP) enzymes [56]. The technology used for CYP inhibition includes luminescence, florescence, radiometric, and HPLC or LC-MS/MS assay. In florescence and luminescence assays, the metabolism of profluorescent or proluminescent substrate by CYP enzyme to give their fluorescent or luminescent product, respectively, is measured in rCYP enzyme. In radiometric method, the release of radiolabel on metabolism of substrate is measured in HLM. In HPLC or LC-MS/MS assay, the concentration of substrate/probe drugs is measured in HLM, HLH, and rCYP enzymes [57].

The in vitro analyses used for P-gp-mediated efflux studies include cytotoxicity assay, accumulation/efflux assays, transport assays, and ATPase assays. In cytotoxicity assays, the IC50 end point (concentration of P-gp substrates or inhibitors) that inhibits the growth of P-gp expressing cells is measured. In accumulation/efflux assay, the accumulation of drugs in P-gp expressing cells is measured. In transport assays, the permeation of drugs from apical-to-basolateral and basolateral-to-apical compartment in polarized epithelial cells is measured, whereas in ATPase assay, the stimulation or inhibition of P-gp ATPase enzyme activity in membranes of P-gp expressed cells is measured [58, 59].

6.2 In vivo models for CYP3A and P-gp-mediated DDI studies

Various strains of mice (including transgenic and knockout), rats, and nonhuman primate (monkey) have been used for CYP3A, P-gp, and dual CYP3A/P-gp-mediated DDI studies [60].

Since midazolam and triazolam are specifically extensively metabolized by CYP3A4 and ketoconazole is a potent inhibitor of CYP3A4, several groups of studies used as model for experimental CYP3A-mediated DDI studies. Moreover, midazolam is not a substrate for P-gp, whereas the ketoconazole can effectively inhibit both CYP3A and P-gp, which can confirm that the interaction between them can be sole attributed to effects on CYP3A. CYP gene knockout and humanized mice have been established for CYP3A-mediated drug interaction using midazolam as substrate [61]. Several strains of rats are most commonly used for CYP3A-mediated drug interaction using midazolam, diltiazem, nifedipine, and doxorubicin as substrates [62, 63]. In addition, cynomolgus monkey was also used as model for CYP3A-mediated DDIs; however, its choice is limited due to its high cost, handling, and ethical concerns [64].

Valspodar, elacridar, and zosuquidar are more selective P-gp inhibitors and thought to be low affinity for CYP enzymes, and other drug transporter proteins are commonly used for in vivo DDI studies in mice and rats. The drugs such as paclitaxel, cyclosporine, and digoxin are most commonly used as substrates for P-gp-mediated inhibition. Moreover, Rho123 is attractive probe and has been widely used as marker to evaluate P-gp functions because it is not a substrate for CYP3A enzyme [65, 66, 67]. The cynomolgus monkey has been also used as model to evaluate effect of P-gp-mediated DDI using erythromycin and fexofenadine as substrate [64, 68].

The evaluation of flavonoid-mediated DDI by using dual substrates of CYP3A and P-gp, inhibitors, and species has been discussed in detail in Section 9 and summarized in Table 1.

Flavonoids Dose-dependent (IC50) inhibition of CYP3A4 activity ↑ Cellular accumulation of rhodamine (MCF-7/ADR cell) References
Quercetin 1.97 μM 3–10 μM [83]
Myricetin 7.8 μM 10–30 μM [84]
Baicalein 9.2 μM 1–10 μM [85]
Baicalein 9.2 mM 10–30 μM [86]
Silibinin 1.8 μM [87]

Table 1.

In vitro effects of some common flavonoids on CYP3A4 and P-gp activity.


7. Flavonoids as P-gp and CYP3A modulators

Flavonoids (a group of polyphenolic compounds) are mainly abundant in vegetables and fruits and routinely consume through our common diet and in the form of beverages (plant-derived), for example, wine and tea [37]. In addition, they are the main constituents of many herbal products/formulations. Structurally, these compounds possess a framework consisting of a chromane ring together with an aromatic ring that is attached at different positions. Based on various substitutions and the oxidation status of the ring C atoms, flavonoids can be categorized into various subclasses, including flavones, flavonols, flavonones, flavanols, isoflavones, and chalcones. Since the last decade, there has been a drastically increase in scientific work on flavonoids, with >2000 publications/year containing “flavonoids” as a keyword found in different literature sources. Flavonoids display antioxidant, anticarcinogenic, antiviral, anti-inflammatory, and antiesterogenic properties, and high intake of flavonoids has been linked with a reduced risk of cancer, cardiovascular disease, osteoporosis, and other age-related degenerative diseases [37, 69].

Due to the wide range of health benefits of flavonoids and their remarkable safety record, numerous herbal preparations containing these compounds are marketed in various formulations as dietary supplements. The total daily intake of flavonoids in the average US diet has been estimated to be more than 1 g [37]. Therefore, the concentration of flavonoid expected to be present is sufficient after the ingestion of flavonoids and/or flavonoid-containing supplements, suggesting a potential herb-drug interaction.

Thus, the consumption of higher doses of flavonoids is common in daily life, and it may increase the risk of pharmacokinetic interactions with clinically used medicine. This concern is also confirmed by increasing evidence, which showed significant or even life-threatening interactions between flavonoids or flavonoid containing products and prescription drugs [70, 71].

Initial publications cite various examples of flavonoids as P-gp transport inhibitors, thereby affecting the bioavailability and cellular uptake of anticancer drugs. These experiments include in vitro analyses of the effects of flavonoids on the intracellular accumulation of P-gp substrates using P-gp-overexpressing cells and a variety of clinical and animal model studies, especially involving P-gp knockout animals [37]. For example, concomitant administration of quercetin increased moxidectin oral bioavailability in lambs [72]; oral bioavailability of quinine was increased by naringin [73]; cyclosporine by baicalein and its aglycone [74]; and paclitaxel by flavones in rats [75]. Similarly, quercetin increased the oral bioavailability of paclitaxel and tamoxifen in rats [76, 77] and digoxin in pigs, which results in high toxicity [78]. All of these studies indicate that flavonoid-P-gp interactions can occur in vivo, resulting in pharmacokinetic interactions. In contrast to the above results, several flavonoids appear to induce P-gp transport, resulting in a decrease in the bioavailability of substrate drugs. For instance, in vitro studies, kaempferol and quercetin, produced inductive effects on P-gp efflux [79, 80], and therefore, the consumption of pure herbal constituents, which contains hypericin, kaempferol, quercetin, and silibinin for 10 days, may produce a significant increase in the expression of P-gp mRNA [81]. In vivo studies have also indicated that long-term exposure (14 days) to St. John’s wort (a flavonoid-containing herbal product) leads to higher expression of MDR1 in the rat intestine [82]. Based on these findings, it has been concluded that chronic exposure to some flavonoids induces intestinal expression of P-gp, resulting in reduced intestinal drug absorption, possibly due to enhanced drug efflux; however, the inhibitory effects on P-gp-mediated efflux are based on short-term exposure. Meanwhile, subsequent in vitro and in vivo studies indicate that the pharmacokinetic interactions of drugs with flavonoids may result in the modulation not only of drug transporters (P-gp) but also of metabolizing enzymes, especially CYP3A, that is, dual inhibition of P-gp and CYP 3A. In vitro studies confirmed that quercetin, myricetin, baicalein, and silibinin were found to produce dose-dependent inhibition of CYP 3A4 activity in CYP inhibition assay and increased the cellular accumulation of rhodamine (MCF-7/ADR cell) in P-gp transport studies [83, 84, 85, 86, 87]. However, in another study, quercetin and rutin were found to induce the function of CYP 3A4 and P-gp, which may lead to increase the bioavailability of substrate drugs [88]. In vitro effects of some common flavonoids on CYP3A4 and P-gp activity are summarized in Table 1. In in vivo studies, coadministration of quercetin, baicalein, silibinin, epigallocatechein, and kaempeferol increased the bioavailability of oral tamoxifen dose dependently through inhibition of P-gp efflux and reduction in the first-pass metabolism through inhibition of CYP3A metabolism in the small intestine and/or liver [78, 84, 89, 90, 91]. Similarly, quercetin, silibinin, naringin, flavone (2-phenyl-4H-1-benzopyran-4-one), genistein, and morin also increased the oral bioavailability of paclitaxel mainly through inhibition of CYP3A4-mediated metabolism in the small intestine and/or liver and inhibition of the P-gp efflux in the small intestine [75, 76, 77, 92, 93, 94]. Additionally, quercetin, myricetin, and baicalein also reduced the bioavailability of doxorubicin by similar mechanism [83, 84, 95]. Similar results were also produced by morin, quercetin, and niringin with diltiazem and baicalein with nimodipine [85, 96, 97, 98]. In contrast, reduced oral bioavailability of tamoxifen by biochanin A and cyclosporine by quercetin and rutin was also reported in rats [88, 99]. In vivo interaction of flavonoids with dual substrates of CYP3A4 and P-gp is summarized in Table 2.

Flavonoids (oral dose) Dual substrate of CYP3A and P-gp (oral dose) Aimals/species Effect on bioavailability parameters References
% change in Cmax % change in AUC Change in RBA* (fold)
Quercetin (2.5 and 7.5 mg/kg) Tamoxifen (10 mg/kg) Rat ↑23–35 ↑ 34–60 ↑1.35–1.61 [78]
Baicalein (0.5, 3, and 10 mg/kg) Tamoxifen (10 mg/kg) Rat ↑ 54.8–100 ↑47.6–89.1 ↑1.47–1.89 [86]
Silibinin (0.5, 2.5, and 10 mg/kg) Tamoxifen (10 mg/kg) Rat ↑45.2–78.6 ↑40.2–71.3 ↑1.40–1.72 [87]
Epigallocatechein (0.5, 3, and 10 mg/kg) Tamoxifen (10 mg/kg) Rat ↑57.1–89.7 ↑48.4–77.0 ↑1.48–1.77 [90]
Kaempeferol (2.5 and 10 mg/kg) Tamoxifen (10 mg/kg) Rat ↑48.9–47.7 ↑39.8–47.7 ↑1.40–1.48 [91]
Biochanin A (100 mg/kg) Tamoxifen (10 mg/kg) Rat ↓23.5 ↓32.3 ↓ 1.32 [99]
Quercetin (2–20 mg/kg, p.o.) Paclitaxel (40 mg/kg) Rat ↑ 1.76–3.29 [76]
Silibinin (0.5, 2.5, and 10 mg/kg) Paclitaxel (40 mg/kg) Rat ↑31.0–52.9 ↑65.8–101.7 ↑1.15–2.02 [87]
Naringin (1, 3, 10, and 20 mg/kg) Paclitaxel (40 mg/kg) Rat ↑1.35–1.69 [92]
Flavone (2–20 mg/kg)** Paclitaxel** (40 mg/kg) Rat ↑2.4–3.1 [75]
Genistein (3.3 and 10 mg/kg) Paclitaxel (30 mg/kg) Rat ↑1.26–1.55 [93]
Morin (3.3–10 mg/kg) Paclitaxel (30 mg/kg) Rat ↑ 70–90 ↑30–70 ↑1.32–1.68 [95]
Quercetin (0.6, 3, and 15 mg/kg) Doxorubicin (50 mg/kg) Rat ↑ 35.1–125.7 ↑ 31.2–136 ↑1.33–2.36 [83]
Myricetin(0.4, 2, and 10 mg/kg) Doxorubicin (40 mg/kg) Rat ↑45–105 ↑51–117 [84]
Baicalein (0.3, 1.5, and 6 mg/kg) Doxorubicin (40 mg/kg) Rat ↑1.20–1.96 [95]
Morin (1.5, 7.5, and 15 mg/kg) Diltiazem (15 mg/kg) Rat ↑ 30–120 1.38–1.80 [96]
Quercetin (2, 10, and 20 mg/kg) Diltiazem (15 mg/kg) Rabbit 1.75–2.76 [97]
Naringin (5 and 15 mg/kg) Diltiazem (15 mg/kg) Rat ↑2.07–2.20 [98]
Quercetin Cyclosporine Rat ↓67.8 ↓43.3 [88]
Rutin Cyclosporine Rat ↓63.2 ↓57.2 [88]
Baicalein (0.4, 2, and 8 mg/kg) Nimodipine (12 mg/kg) Rat ↑1.39–1.58 [85]

Table 2.

In vivo interaction of some common flavonoids with dual substrates of CYP3A and P-gp.

RBA, relative bioavailability.

Flavone, 2-phenyl-4H-1-benzopyran-4-one.


8. Significance of flavonoids as P-gp and CYP3A inhibitors

Various experimental and clinical studies confirmed that flavonoids produce antioxidant, anti-inflammatory, and anticarcinogenic effects. Studies also confirmed that these effects were attributed due to their inhibitions of efflux transporter enzyme (P-gp) and/or drug metabolizing enzyme (CYP3A). Therefore, flavonoids as P-gp inhibitor may use with other chemotherapeutic drugs for cancer treatment [100]. Occurrence of P-gp protein in various body tissues affects the absorption, distribution, metabolism, and excretion of drugs. Therefore, the dual effect of anticarcinogenic and P-gp modulation may synergistically act for the treatment of cancer [101]. The chemotherapeutic treatment of metastatic brain tumors is limited due to its low distribution in brain tissue by blood brain barrier and blood-cerebrospinal fluid barrier. P-gp is presented in the apical membranes of these cells, and flavonoids can improve the permeation of chemotherapeutic drugs by inhibiting the P-gp-mediated efflux [102]. Flavonoids can be used as nontoxic P-gp and/or CYP3A inhibitors and by its coadministration could improve the bioavailability of poorly unavailable drugs, especially for anticancer drugs, by interfering its clearance or inhibiting its metabolism [103]. P-gp presents in bile canaliculi and kidney suggested that it can also play a role in biliary and renal elimination of drugs. Coadministration of flavonoids (as P-gp inhibitors) can reduce the clearance of anticancer drugs, for example, vinblastine, doxorubicin, and irinotecan [104, 105]. Flavonoids can also play an important role in reversal of MDR in cancer chemotherapy. P-gp-associated MDR is a serious concern for limitation of cancer treatment. P-gp occurrence in tumor cell has been extensively characterized, and its overexpression has been confirmed during relapse. Therefore, it can be concluding that P-gp inhibitors (flavonoids) can potentially reverse the MDR during cancer chemotherapy [106].


9. Tyrosine kinase inhibitors

The evidence of protein tyrosine kinase enzyme involvement in tumor development makes it novel targets for selective chemotherapy and thus target for rational design of drug development. Now protein kinases, especially tyrosine kinases, are being used as main targets for drug development related to malignancy, resulting in the high approval rate of various TKIs by the FDA [24, 107]. Imatinib was the first of its kind, which was introduced clinically, followed by various molecules such as gefitinib, erlotinib, sorafenib, afatinib, nilotinib, bosutinib, crizotinib, ponatinib, lapatinib, sunitinib, and dasatinib, and many more are in pipeline [108]. Although mechanism of action of these compounds is same, that is, competitive ATP inhibition at the catalytic binding site of tyrosine kinases, they differ from each other in the spectrum of targeted kinase activity, pharmacokinetic profile, and compound-specific adverse effects [109]. These TKIs have been developed in oral formulations, are administered on a daily basis, and usually prescribed at a fixed dose. Although oral administration may be convenient for patients as it can reduce health care costs, improve quality of life of patients, and avoid heavy burden of day-stay infusion units, this practice also displays a disadvantage, in that the oral bioavailability of most of TKIs is highly dependent on their absorption through gastrointestinal tract and first-pass hepatic metabolism [25, 107].

Almost all TKIs are rapidly absorbed, and their maximum plasma concentration (Cmax) was achieved in 3–6 h after oral administration except sunitinib (6–12 h). Food intake has no significant effect on the absorption of imatinib, dasatinib, gefitinib, sorafenib, or sunitinib. However, the bioavailability of lapatinib and nilotinib is increased pronouncedly with food intake. Almost all TKIs are high to plasma protein (>90%) and therefore extensively distribute into tissues resulting in large volume of distribution and prolong terminal half-life. Excretion of TKIs is predominantly through feces, and only a small fraction is eliminated with urine. Almost all TKIs are dual substrates of CYP3A4 (the most abundant CYP in the human liver and intestine) and P-gp efflux transporter, except sorafenib, vandetanib, bosutinib, ibrutinib, cabozantinib, regorafenib, and ruxolitinib, which are only substrate of CYP3A4, whereas vemurafenib and afatinib, which are effluxed by P-gp only [24, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121]. Table 3 summarizes the substrate potential of TKIs with CYP3A4 and/or P-gp.

TKIS CYP 3A4 P-gp References
Imatinib [108, 110, 111]
Gefitinib [24, 108, 115, 118]
Erlotinib [24, 118]
Sorafenib X [24, 108, 118]
Dasatinib [24, 108, 118]
Sunitinib [24, 108, 118]
Lapatinib [24, 108, 118]
Nilotinib [24, 108]
Crizotinib [108, 111, 118]
Vandetanib X [108, 111]
Vemurafenib X [108, 112, 118]
Axitinib [108, 111, 118]
Bosutinib X [108, 111, 118]
Pazopanib [108, 111, 118]
Ponatinib [108, 111, 118]
Dabrafenib [108, 111, 118]
Cediranib [114, 118]
Tandutinib NA [118]
Ibrutinib X [116, 121]
Afatinib X [108, 111]
Cabozantinib X [108, 111]
Regorafenib X [108, 111]
Ruxolitinib X [108, 117]
Osimertinib [120]

Table 3.

Substrate potential of TKIs with CYP3A4 and/or P-gp.


10. Drug-drug interaction with TKI

DDIs represent a serious concern, especially for agents that influenced by efflux transporters and CYP3A4 enzyme, and can produce clinically relevant drug interactions by alteration of its bioavailability. Because the majority of TKIs are substrate of CYP3A4 and/or P-gp, DDI with CYP3A4 and/or P-gp inhibitors and inducers must be taken into account, and they must be used with caution, as advised in the package insert. Recently, it has been reported that coprescription of those medicines, which may induce or inhibit the metabolic pathways used by TKIs, is very high. Overall coprescribing rates of drugs that induce metabolism of TKI and may lead to decrease the effectiveness of TKIs ranged from 23 to 57%, whereas coprescribing rates of drugs that inhibit metabolism of TKIs and may increase its toxicity ranged from 24 to 74% [122]. For example, coadministration of imatinib with dual inhibitors CYP3A4 and P-gp increases not only the plasma concentration but also the intracellular concentration of imatinib. Dual inhibitors CYP3A4 and P-gp, such as verapamil fluconazole, itraconazole [123], erythromycin, clarithromycin [124], cyclosporine [125], and ketoconazole [126], increased the intracellular concentration of imatinib by inhibiting both its CYP3A4-mediated metabolism and its efflux through P-gp, which might result in increasing its cellular toxicity. Moreover, P-gp-mediated efflux inhibition by proton pump inhibitors, such as pantoprazole, has reported to increase the brain concentration of imatinib [127]. In contrast, coadministration of CYP3A4 inducers, such as rifampicin or certain antiepileptics, may lead to a reduction in imatinib exposure of up to 74% [24, 110]. Similarly, inhibitors of both CYP3A4 and P-gp increase both the plasma and intracellular concentrations of dasatinib as well, which are also expected to occur for verapamil, erythromycin, clarithromycin, fluconazole, itraconazole [123], cyclosporine [125], and ketoconazole [123, 128]. Concomitant administration of the CYP3A4 inducer rifampicin leads to a reduction in dasatinib exposure of 80% [24, 129, 130]. The area under curve (AUC) of nilotinib is increased 3-fold in healthy subjects receiving ketoconazole [130], whereas coadministration of CYP3A4 inducers, such as rifampicin, leads to a 4.8-fold reduction in nilotinib exposure [24, 129, 130]. Administration of gefitinib in the presence of rifampicin reduces the AUC of gefitinib by 83%, while in the presence of itraconazole, the AUC of gefitinib is increased by 78% [24, 131]. Furthermore, coadministration of ketoconazole results in a 3.6-fold increase in lapatinib plasma exposure, whereas coadministration of carbamazepine results in a decrease in the AUC of lapatinib by 72% [24, 132]. Although the result of above studies confirmed the risk of frequent DDIs among TKIs, but did not addressed the clinical consequences of these, that is, increased toxicity or therapeutic failure. Moreover, in some cases, in spite of knowing, these potential interacting combinations could have been intentionally prescribed by physicians because they considered the potential benefits to outweigh the risks or because the patient had the ability to tolerate these combinations in the past [133]. Since most of these TKIs are relatively new, their scientific evidence that supports their DDIs is limited. Therefore, it is not unexpected to observe that medical oncologists are not able to report TKI DDI pairs, which might have a high probability of causing deleterious effects in the treatment of cancer patients [134].

11. Flavonoids and TKI interaction

Compounds that are capable of inhibiting the activity of tyrosine kinase receptors (RTKs) are expected to display antiproliferative properties. Various in vitro and in vivo studies suggested that most of the flavonoids quercetin, genistein, hesperidin, and naringenin have TKI properties, which play a significant role in its anticancer effects [135, 136, 137, 138]. Due to antiproliferative properties, flavonoids can be use along with conventional TKIs in clinical practice and therefore it definitely raise concern of pharmacokinetic interaction. So, it is understood that similar to conventional medicines, flavonoids act as dual modulators of CYP3A4 and P-gp, which may produce significant effects on the disposition kinetics of TKIs. In spite of that, limited data are available relevant to interaction of flavonoids with TKIs in the literature. St. John’s wort that contains numerous flavonoids was found to increase imatinib clearance by 43% and decrease its AUC and Cmax by 30 and 29%, respectively [139, 140] in human subjects. Similarly, St. John’s wort may also decrease the plasma concentration of dasatinib, and its use is discouraged in patients receiving it [141]. Genistein (isoflavone) when administered for 15 days significantly decreased the Cmax and AUC of imatinib, whereas its single dose did not produce any effects in rats [142]. Silybin, a constituent of silymarin, also decreased the AUC of imatinib after multiple dose administration (15 days) in rats [143]. However, apigenin in single dose increased the AUC of imatinib but decreased it in multiple dose administration (15 days) in rats [144], which suggests that apigenin may act as enzyme inhibitor in single dose and become inducer after long-term administration. Epigallocatechin-3-gallate also decreased the Cmax and AUC of sunitinib after single dose administration in rats [145]. However, Bas 100, a novel mechanism-based CYP3A4 inhibitor, isolated from grapefruit juice increased 2.1-fold AUC of erlotinib after single dose administration [146]. Similar effects were produced by the intake of 240 ml of grapefruit juice (an inhibitor of CYP3A4 and P-gp), which are shown to increase the nilotinib AUC by 60%, and thus, coadministration of nilotinib with grapefruit juice is not recommended [147]. Additionally, a case study showed that patients who had already developed resistance to gefitinib treatment become responsive after the withdrawal of all CAMs [148]. Table 4 summarizes the pharmacokinetic interaction of flavonoids or flavonoids containing herbal constituents with TKIs in both experimental animals and clinical studies.

Flavonoids/constituents TKI inhibitors Model Pharmacokinetic effects References
St. John’s wort (300 mg, p.o) Imatinib (400 mg, p.o.) Healthy volunteers ↓AUC (30%)
↑ Oral clearance (43%)
St. John’s wort (300 mg, p.o) Imatinib (400 mg, p.o.) Healthy volunteers ↓AUC (30%)
↓ Cmax (29%)
Genistein (50, 100 mg/kg, p.o.) for 15 days Imatinib (30 mg/kg, p.o.) Rat ↓AUC (27–28%)
↓ Cmax (23–25%)
Genistein (50, 100 mg/kg, p.o.) single dose Imatinib (30 mg/kg, p.o.) Rat No effects [142]
Apigenin (165 mg/kg, p.o) for 15 days Imatinib (30 mg/kg, p.o.) Rat ↓AUC (25%) [144]
Apigenin (165 and 252 mg/kg, p.o) single dose Imatinib (30 mg/kg, p.o.) Rat ↑ AUC (25–40%) [144]
Silybin (50 mg/kg, single and multiple for 15 days, p.o. Imatinib (p.o.) Rat ↓ AUC significantly [143]
BAS 100 (10 mg /kg, p.o.) Erlotinib 10 mg /kg, p.o.) Mice ↑ AUC (2.1 fold) [146]
Epigallocatechin-3-gallate (100 mg /kg, p.o.) Sunitinib (30 mg/kg, p.o.) Rats ↓Cmax (47.7%) ↓AUC (51.5%) [145]
Grapefruit juice (240 mL), p.o Nilotinib (400 mg, p.o.) Healthy volunteers ↑ AUC (29%)
↑ Cmax (60%)

Table 4.

In vivo pharmacokinetic interaction of flavonoids or flavonoids containing herbal constituents with TKIs.

12. Conclusions

The CYP3A enzyme accounts approximately 30% of hepatic and more than 70% of intestinal CYP activity. P-gp efflux protein is encoded by ABCB1 gene (MDR1) and is responsible for cellular efflux of numerous drugs. PXR regulates both CYP3A and P-gp and coordinately mediates detoxification of many xenobiotics during oral absorptions. The flavonoid constituent-mediated modulation of CYP3A and P-gp is the main mechanism through which the bioavailability and disposition of conventional drugs are regulated. The synergistically modulation of CYP3A and P-gp by flavonoids may increase the potency of chemotherapeutic drugs. Moreover, it increases the permeability of drugs in brain and reduces the MDR in cancer chemotherapy. Most of the TKIs are oral dosage formulations and also dual substrates of CYP3A and P-gp, so the risk of pharmacokinetic interactions with flavonoids is expected on concurrent administration. Therefore, there is a compelling need to study the cellular and molecular mechanisms involved in the flavonoid-mediated modulation of CYP3A and P-gp and their expected impact on the exposure and disposition of TKIs. Results from some experimental and clinical studies have confirmed the interaction between TKIs and flavonoids, but these unwanted clinical consequences in cancer patients have not been elaborated. However, even small changes in drug metabolism and pharmacokinetics of TKIs may lead to therapeutic failure or toxicity in cancer patients. Nevertheless, it is a challenging task to determine the clinical effects of the DDI due to the large interpatient variability in the pharmacokinetics of the TKIs.

Conflict of interest

The author declares that there is no conflict of interest.


  1. 1. Bhattaram VA, Graefe U, Kohlert C, Veit M, Derendorf H. Pharmacokinetics and bioavailability of herbal medicinal products. Phytomedicine. 2002;9(Suppl 3):1-33
  2. 2. Mukherjee PK, Wahile A. Integrated approaches towards drug development from Ayurveda and other Indian system of medicines. Journal of Ethnopharmacology. 2006;103:25-35
  3. 3. Robinson MM, Zhang X. The world medicines situation. In: Traditional Medicines: Global Situation, Issues and Challenges. Geneva: World Health Organization; 2011. pp. 1-12
  4. 4. Citarasu T. Herbal biomedicines: A new opportunity for aquaculture industry. Acquaculture International. 2010;18:403-414
  5. 5. David B, Wolfender J, Dias DA. The pharmaceutical industry and natural products: Historical status and new trends. Phytochemistry Reviews. 2015;14:299-315
  6. 6. Ghani A. Herbal Medicines: Present Status, Future Prospects. October 17, 2013. Available from: http://www.phar [Accessed: 20 January 2017]
  7. 7. Pal D, Mitra AK. MDR- and CYP3A4-mediated drug-herbal interactions. Life Sciences. 2006;78:2131-2145
  8. 8. Li Y, Revalde J, Paxton JW. The effects of dietary and herbal phytochemicals on drug transporters. Advanced Drug Delivery Reviews. 2017;116:45-62. DOI: 10.1016/j.addr.2016.09.004
  9. 9. Strandell J, Neil A, Carlin G. An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies. Phytomedicine. 2004;11:98-104
  10. 10. Evans AM. Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Therapeutic Drug Monitoring. 2000;22:131-136
  11. 11. Ioannides C. Pharmacokinetic interactions between herbal remedies and medicinal drug. Xenobiotica. 2002;32:451-478
  12. 12. Wilkinson GR. The effects of diet, aging and disease-states on presystemic elimination and oral drug bioavailability in human. Advanced Drug Delivery Reviews. 1997;27:129-159
  13. 13. Fugh-Berman A. Herb–drug interactions. Lancet. 2000;355:134-138
  14. 14. Fugh-Berman A, Ernst E. Herb–drug interactions: Review and assessment of report reliability. British Journal of Clinical Pharmacology. 2001;52:587-595
  15. 15. Cushnie TPT, Lamb AJ. Recent advances in understanding the antibacterial properties of flavonoids. International Journal of Antimicrobial Agents. 2011;38:99-107
  16. 16. García-Lafuente A, Guillamón E, Villares A, Rostagno MA, Martínez JA. Flavonoidsas anti-inflammatory agents: Implications in cancer and cardiovascular disease. Inflammation Research. 2009;58:537-552
  17. 17. Brantley SJ, Argikar AA, Lin YS, Nagar S, Paine MF. Herb-drug interactions: Challenges and opportunitiesfor improved predictions. Drug Metabolism and Disposition. 2014;42:301-317
  18. 18. Sahu K, Siddiqui AA, Shaharyar M, Malik S. Pharmacokinetic interaction between febuxostat and morin in rats. Expert Opinion on Drug Metabolism & Toxicology. 2014;10:307-312
  19. 19. Kumar KK, Priyanka L, Gnananath K, Babu PR, Sujatha S. Pharmacokinetic drug interactions between apigenin, rutin and paclitaxel mediated by P-glycoprotein in rats. European Journal of Drug Metabolism and Pharmacokinetics. 2015;40:267-276
  20. 20. Ferreira A, Pousinho S, Fortuna A, Falcao A, Alves G, et al. Phytochemistry Reviews. 2014;14:233-272
  21. 21. Gufford BT, Chen G, Lazarus PTN, Graf NH, Paine MF. Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation. Drug Metabolism and Disposition. 2014;42:1675-1683
  22. 22. Neul C, Schaeffeler E, Sparreboom A, Laufer S, Schwab M, Nies AT. Impact of membrane drug transporters on resistance to small-molecule tyrosine kinase inhibitors. Trends in Pharmacological Sciences. 2016;37:904-932
  23. 23. Shao J, Markowitz JS, Bei D, An G. Enzyme- and transporter-mediated drug interactions with small molecule tyrosine kinase inhibitors. Journal of Pharmaceutical Sciences. 2014;103:3810-3833
  24. 24. van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treatment Reviews. 2009;35:692-706
  25. 25. Pajares B, Torres E, Trigo JM, Sáez MI, Ribelles N, Jiménez B, et al. Tyrosine kinase inhibitors and drug interactions: A review with practical recommendations. Clinical & Translational Oncology. 2012;14:94-101
  26. 26. Kim SK, Ovak RF. The role of intracellular signaling in insulinmediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacology & Therapeutics. 2007;113:88-120
  27. 27. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. The Lancet. 2002;360:1155-1162
  28. 28. Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, Guzelian PS. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. The Journal of Clinical Investigation. 1987;80:1029-1036
  29. 29. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. The Journal of Clinical Investigation. 1992;90:1871-1878
  30. 30. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Inter individual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals studies with liver microsomes of 30 Japanese and 30 Caucasians. The Journal of Pharmacology and Experimental Therapeutics. 1994;270:414-423
  31. 31. de Waziers I, Cugnenc PH, Yang CS, Leroux JP, Beaune PH. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. The Journal of Pharmacology and Experimental Therapeutics. 1990;253:387-394
  32. 32. Centre for Drug Evaluation and Research (CDER). Draft Guideline for In Vitro Metabolism- and Transporter Mediated Drug-Drug Interaction. 2017. Available from:
  33. 33. Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y. Prediction of pharmacokinetic alterations caused by drug-drug interactions: Metabolic interaction in the liver. Pharmacological Reviews. 1998;50(3):387-412
  34. 34. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ. Drug metabolism and drug interactions: Application and clinical value of in vitro models. Current Drug Metabolism. 2003;4(5):423-459. DOI: 10.2174/1389200033489361
  35. 35. Loo TW, Clarke DM. Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux. The Journal of Membrane Biology. 2005;206:173-185
  36. 36. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nature Reviews. Cancer. 2002;2(1):48-58
  37. 37. Morris ME, Zhang S. Flavonoid-drug interactions: Effects of flavonoids on ABC transporters. Life Sciences. 2006;78:2116-2130
  38. 38. Cordon-Cardo C, O'Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(2):695-698
  39. 39. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P- glycoprotein in normal human tissues. Proceedings of the National Academy of Sciences of the United States of America. 1987;84:7735-7738
  40. 40. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: Evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. The Journal of Histochemistry and Cytochemistry. 1989;37:159-164
  41. 41. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annual Review of Biochemistry. 1993;62:385-427
  42. 42. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution andpharmacokinetics of dexamethasone, digoxin, and cyclosporin A. The Journal of Clinical Investigation. 1995;96:1698-1705
  43. 43. Lee CG, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang KT, Ambudkar SV, et al. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry. 1998;37:3594-3601
  44. 44. Meador J, Sweet P, Stupecky M, Wetzel M, Murray S, Gupta S, et al. Enhancement by cyclosporin A of daunorubicin efficacy in Ehrlich ascites carcinoma and murine hepatoma. Cancer Research. 1987;47:6216-6219
  45. 45. Horio M, Chin KV, Currier SJ, Goldenberg S, Williams C, Pastan I, et al. Transepithelial transport of drugs by the multidrug transporter in cultured Madin–Darby canine kidney cell epithelia. The Journal of Biological Chemistry. 1989;264:14880-14884
  46. 46. Christians U, Schmitz V, Haschke M. Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opinion on Drug Metabolism & Toxicology. 2005;1(4):641-654
  47. 47. van Waterschoot RA, Lagas JS, Wagenaar E, van der Kruijssen CM, van Herwaarden AE, Song JY, et al. Absence of both cytochrome P450 3A and P-glycoprotein dramatically increases docetaxel oral bioavailability and risk of intestinal toxicity. Cancer Research. 2009;69:8996-9002
  48. 48. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Molecular Carcinogenesis. 1995;13:129-134
  49. 49. van Waterschoot RA, Schinkel AH. A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: Recent insights from knockout and transgenic mice. Pharmacological Reviews. 2011;63:390-410
  50. 50. Benet LZ. The drug transporter-metabolism alliance: Uncovering and defining the interplay. Molecular Pharmaceutics. 2009;6:1631-1643
  51. 51. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. The Journal of Pharmacology and Experimental Therapeutics. 2002;302(2):645-650
  52. 52. Lutz JD, Kirby BJ, Wang L, Song Q , Ling J, Massetto B, et al. Cytochrome P450 3A induction predicts P-glycoprotein induction. Part 1: Establishing induction relationships using ascending dose rifampin. Clinical Pharmacology and Therapeutics. 2018;104(6):1182-1190
  53. 53. Rosenfeld JM, Vargas R Jr, Xie W, Evans RM. Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor. Molecular Endocrinology. 2003;17(7):1268-1282
  54. 54. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA. Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Molecular Pharmacology. 2002;62(3):638-646
  55. 55. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Medicine. 2001;7(5):584-590
  56. 56. Riley RJ, Kenna JG. Cellular models for ADMET predictions and evaluation of drug-drug interactions. Current Opinion in Drug Discovery & Development. 2004;7(1):86-99
  57. 57. Fowler S, Zhang H. In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: Current status on methodologies and their utility for predicting drug-drug interactions. The AAPS Journal. 2008;10(2):410-424. DOI: 10.1208/s12248-008-9042-7
  58. 58. Muenster U, Grieshop B, Ickenroth K, Gnoth MJ. Characterization of substrates and inhibitors for the in vitro assessment of Bcrp mediated drug-drug interactions. Pharmaceutical Research. 2008;25(10):2320-2326. DOI: 10.1007/s11095-008-9632-1
  59. 59. Hochman JH, Yamazaki M, Ohe T, Lin JH. Evaluation of drug interactions with P-glycoprotein in drug discovery: In vitro assessment of the potential for drug-drug interactions with P-glycoprotein. Current Drug Metabolism. 2002;3(3):257-273. DOI: 10.2174/1389200023337559
  60. 60. Marathe PH, Rodrigues AD. Multi-drug resistance in cancer. In: Zhou J, editor. Methods in Molecular Biology. Vol. 56. Humana Press; 2010
  61. 61. Granvil CP, Yu AM, Elizondo G, et al. Expression of the human CYP3A4 gene in the small intestine of transgenic mice: In vitro metabolism and pharmacokinetics of midazolam. Drug Metabolism and Disposition. 2003;31(5):548-558. DOI: 10.1124/dmd.31.5.548
  62. 62. Ogasawara A, Kume T, Kazama E. Effect of oral ketoconazole on intestinal first-pass effect of midazolam and fexofenadine in cynomolgus monkeys. Drug Metabolism and Disposition. 2007;35(3):410-418. DOI: 10.1124/dmd.106.011288
  63. 63. Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: Inhibition of CYP3A4 activity by oxidized diltiazem metabolites. The Journal of Pharmacology and Experimental Therapeutics. 1997;282(1):294-300
  64. 64. Yamano K, Yamamoto K, Kotaki H, Sawada Y, Iga T. Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats: Implication of concentrative uptake of inhibitors into liver. Drug Metabolism and Disposition. 1999;27(3):395-402
  65. 65. Schinkel AH, Mol CA, Wagenaar E, van Deemter L, Smit JJ, Borst P. Multidrug resistance and the role of P-glycoprotein knockout mice. European Journal of Cancer. 1995;31A(7-8):1295-1298. DOI: 10.1016/0959-8049(95)00130-b
  66. 66. Kemper EM, Verheij M, Boogerd W, Beijnen JH, van Tellingen O. Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein. European Journal of Cancer. 2004;40(8):1269-1274. DOI: 10.1016/j.ejca.2004.01.024
  67. 67. Yumoto R, Murakami T, Sanemasa M, Nasu R, Nagai J, Takano M. Pharmacokinetic interaction of cytochrome P450 3A-related compounds with rhodamine 123, a P-glycoprotein substrate, in rats pretreated with dexamethasone. Drug Metabolism and Disposition. 2001;29(2):145-151
  68. 68. Ward KW, Azzarano LM. Preclinical pharmacokinetic properties of the P-glycoprotein inhibitor GF120918A (HCl salt of GF120918, 9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the mouse, rat, dog, and monkey. The Journal of Pharmacology and Experimental Therapeutics. 2004;310(2):703-709. DOI: 10.1124/jpet.104.068288
  69. 69. Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacology & Therapeutics. 2002;96:67-202
  70. 70. Bailey DG, Arnold JM, Munoz C, Spence JD. Grapefruit juice--felodipine interaction: Mechanism, predictability, and effect of naringin. Clinical Pharmacology and Therapeutics. 1993;53:637-642
  71. 71. Ducharme MP, Warbasse LH, Edwards DJ. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clinical Pharmacology and Therapeutics. 1995;57:485-491
  72. 72. Dupuy J, Lespine A, Sutra JF, Alvinerie M. Fumagillin a new P-glycoprotein-interfering agent able to modulate moxidectin efflux in rat hepatocytes. Journal of Veterinary Pharmacology and Therapeutics. 2006;29:489-494
  73. 73. Zhang H, Wong CW, Coville PF, Wanwimolruk S. Effect of the grapefruit flavonoid naringin on pharmacokinetics of quinine in rats. Drug Metabolism and Drug Interactions. 2000;17:351-363
  74. 74. Lai MY, Hsiu SL, Hou YC, Tsai SY, Chao PD. Significant decrease of cyclosporine bioavailability in rats caused by a decoction of the roots of Scutellaria baicalensis. Planta Medica. 2004;70:132-137
  75. 75. Choi JS, Choi HK, Shin SC. Enhanced bioavailability of paclitaxel after oral coadministration with flavone in rats. International Journal of Pharmaceutics. 2004a;275:165-170
  76. 76. Choi JS, Jo BW, Kim YC. Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. European Journal of Pharmaceutics and Biopharmaceutics. 2004b;57:313-318
  77. 77. Wang YH, Chao PD, Hsiu SL, Wen KC, Hou YC. Lethal quercetin-digoxin interaction in pigs. Life Sciences. 2004;74:1191-1197
  78. 78. Shin SC, Choi JS, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. International Journal of Pharmaceutics. 2006;313:144-149
  79. 79. Chieli E, Romiti N, Cervelli F, Tongiani R. Effects of flavonols on P-glycoprotein activity in cultured rat hepatocytes. Life Sciences. 1995;57:1741-1751
  80. 80. Shapiro AB, Ling V. Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochemical Pharmacology. 1997;53:587-596
  81. 81. Patel J, Buddha B, Dey S, Pal D, Mitra AK. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents: Changes in P-gp and CYP3A4 activity. American Journal of Therapeutics. 2004;11:262-277
  82. 82. Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, et al. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clinical Pharmacology and Therapeutics. 2000;68:598-604
  83. 83. Choi JS, Piao YJ, Kang KW. Effects of quercetin on the bioavailability of doxorubicin in rats: Role of CYP3A4 and P-gp inhibition by quercetin. Archives of Pharmacal Research. 2011a;34:607-613
  84. 84. Choi JS, Shin SC, Choi JS. Effects of myricetin on the bioavailability of doxorubicin for oral drug delivery in rats: Possible role of CYP3A4 andP-glycoprotein inhibition by myricetin. Archives of Pharmacal Research. 2011b;34:309-315
  85. 85. Cho YA, Choi JS, Burm JP. Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats: A possible role of P-glycoprotein and CYP3A4 inhibition by baicalein. Pharmacological Reports. 2011;63:1066-1073
  86. 86. Li C, Kim M, Choi H, Choi J. Effects of baicalein on the pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats: Possible role of cytochrome P450 3A4 and P-glycoprotein inhibition by baicalein. Archives of Pharmacal Research. 2009;64:579-583
  87. 87. Lee CK, Choi JS. Effects of silibinin, inhibitor of CYP3A4 and P-glycoprotein in vitro, on the pharmacokinetics of paclitaxel after oral and intravenous administration in rats. Pharmacology. 2010;85:350-356
  88. 88. Yu CP, Wu PP, Hou YC, Lin SP, Tsai SY, Chen CT, et al. Quercetin and rutin reduced the bioavailability of cyclosporine from Neoral, an immunosuppressant, through activating P-glycoprotein and CYP 3A4. Journal of Agricultural and Food Chemistry. 2011;59:4644-4648
  89. 89. Kim CS, Choi SJ, Park CY, Li C, Choi JS. Effects of silybinin on the pharmacokinetics of tamoxifen and its active metabolite, 4-hydroxytamoxifen in rats. Anticancer Research. 2010;30:79-85
  90. 90. Shin SC, Choi JS. Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Anti-Cancer Drugs. 2009;20:584-588
  91. 91. Piao Y, Shin SC, Choi JS. Effects of oral kaempferol on the pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, after oral administration of tamoxifen to rats. Biopharmaceutics & Drug Disposition. 2008;29:245-249
  92. 92. Choi JS, Shin SC. Enhanced paclitaxel bioavailability after oral coadministration of paclitaxel prodrug with naringin to rats. International Journal of Pharmaceutics. 2005;292:149-156
  93. 93. Li X, Choi JS. Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats. International Journal of Pharmaceutics. 2007;337:188-193
  94. 94. Choi BC, Choi JS, Han HK. Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats. International Journal of Pharmaceutics. 2006;323:81-85
  95. 95. Shin SC, Li C, Choi JS. Effects of baicalein, an antioxidant, on the bioavailability of doxorubicin in rats: Possible role of P-glycoprotein inhibition by baicalein. Die Pharmazie. 2009;64:579-583
  96. 96. Choi JS, Han HK. Pharmacokinetic interaction between diltiazem and morin, a flavonoid, in rats. Pharmacological Research. 2005;52:386-391
  97. 97. Choi JS, Li X. Enhanced diltiazem bioavailability after oral administration of diltiazem with quercetin to rabbits. International Journal of Pharmaceutics. 2005;297:1-8
  98. 98. Choi JS, Han HK. Enhanced oral exposure of diltiazem by the concomitant use of naringin in rats. International Journal of Pharmaceutics. 2005;305:122-128
  99. 99. Singh SP, Wahajuddin M, Raju KS, Ali MM, Kohli K, Jain GK. Reduced bioavailability of tamoxifen and its metabolite 4-hydroxytamoxifen after oral administration with biochanin A (an isoflavone) in rats. Phytotherapy Research. 2012;26:303-307
  100. 100. Bansal T, Jaggi M, Khar RK, Talegaonkar S. Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy. Journal of Pharmacy & Pharmaceutical Sciences. 2009;12(1):46-78. DOI: 10.18433/j3rc77
  101. 101. Bansal T, Jaggi M, Khar RK, Talegaonkar S. Status of flavonols as P-glycoprotein inhibitors in cancer chemotherapy. Current Cancer Therapy Reviews. 2009;5(2):46-78. DOI: 10.2174/157339409788166742
  102. 102. Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. The Journal of Pharmacology and Experimental Therapeutics. 2003;304(3):1085-1092. DOI: 10.1124/jpet.102.045260\
  103. 103. Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). The Oncologist. 2007;12(8):927-941. DOI: 10.1634/theoncologist.12-8-927
  104. 104. Iyer L, Ramírez J, Shepard DR, et al. Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice. Cancer Chemotherapy and Pharmacology. 2002;49(4):336-341. DOI: 10.1007/s00280-001-0420-4
  105. 105. Tobin PJ, Hong Y, Seale JP, Rivory LP, McLachlan AJ. Loperamide inhibits the biliary excretion of irinotecan (CPT-11) in the rat isolated perfused liver. The Journal of Pharmacy and Pharmacology. 2005;57(1):39-45. DOI: 10.1211/0022357055100
  106. 106. Goldstein LJ, Galski H, Fojo A, et al. Expression of a multidrug resistance gene in human cancers. Journal of the National Cancer Institute. 1989;81(2):116-124. DOI: 10.1093/jnci/81.2.116
  107. 107. Klümpen HJ, Samer CF, Mathijssen RH, Schellens JH, Gurney H. Moving towards dose individualization of tyrosine kinase inhibitors. Cancer Treatment Reviews. 2011;37:251-260
  108. 108. Herbrink M, Nuijen B, Schellens JH, Beijnen JH. Variability in bioavailability of small molecular tyrosine kinase inhibitors. Cancer Treatment Reviews. 2015;41:412-422
  109. 109. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors—A review on pharmacology, metabolism and side effects. Current Drug Metabolism. 2009;10:470-481
  110. 110. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clinical Pharmacokinetics. 2005;44:879-894
  111. 111. Shukla S, Sauna ZE, Ambudkar SV. Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia. 2008;22:445-447
  112. 112. MacLeod AK, McLaughlin LA, Henderson CJ, Wolf CR. Activation status of the pregnane X receptor influences vemurafenib availability in humanized mouse models. Cancer Research. 2015;75:4573-4581
  113. 113. Suttle AB, Grossmann KF, Ouellet D, Richards-Peterson LE, Aktan G, Gordon MS, et al. Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib. Journal of Clinical Pharmacology. 2015;55:392-400
  114. 114. Lassen U, Miller WH, Hotte S, Evans TR, Kollmansberger C, Adamson D, et al. Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours. Cancer Chemotherapy and Pharmacology. 2013;71:543-549
  115. 115. Teo YL, Ho HK, Chan A. Metabolism-related pharmacokinetic drug-drug interactions with tyrosine kinase inhibitors: Current understanding, challenges and recommendations. British Journal of Clinical Pharmacology. 2015;79:241-253
  116. 116. Marostica E, Sukbuntherng J, Loury D, de Jong J, de Trixhe XW, Vermeulen A, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemotherapy and Pharmacology. 2015;75:111-121
  117. 117. Shi JG, Chen X, Emm T, Scherle PA, McGee RF, Lo Y, et al. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. Journal of Clinical Pharmacology. 2012;52:809-818
  118. 118. Deng J, Shao J, Markowitz JS, An G. ABC transporters in multi-drug resistance and ADME-Tox of small molecule tyrosine kinase inhibitors. Pharmaceutical Research. 2014;31:2237-2255
  119. 119. Scheffler M, Di Gion P, Doroshyenko O, Wolf J, Fuhr U. Clinical pharmacokinetics of tyrosine kinase inhibitors: Focus on 4-anilinoquinazolines. Clinical Pharmacokinetics. 2011;50:371-403
  120. 120. US Prescribing Information of TAGRISSO™ (Osimertinib) Tablets. 2015. Available from: [Accessed: 18 January 2017]
  121. 121. US Prescribing Information of IMBRUVICA® (Ibrutinib) Capsules, for Oral Use. 2016. Available from: [Accessed: 18 January 2017]
  122. 122. Bowlin SJ, Xia F, Wang W, Robinson KD, Stanek EJ. Twelve-month frequency of drug-metabolizing enzyme and transporter-based drug-drug interaction potential in patients receiving oral enzyme-targeted kinase inhibitor antineoplastic agents. Mayo Clinic Proceedings. 2013;88:139-148
  123. 123. Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117:e75-e87
  124. 124. Azuma M, Nishioka Y, Aono Y, Inayama M, Makino H, Kishi J, et al. Role of alpha1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice. American Journal of Respiratory and Critical Care Medicine. 2007;176:1243-1250
  125. 125. Yokota A, Kimura S, Masuda S, et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood. 2007;109:306-314
  126. 126. Dutreix C, Peng B, Mehring G, et al. Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemotherapy and Pharmacology. 2004;54:290-294
  127. 127. Breedveld P, Pluim D, Cipriani G, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): Implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Research. 2005;65:2577-2582
  128. 128. Johnson FM, Agrawal S, Burris H, et al. Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors. Cancer. 2010;116:1582-1591
  129. 129. Tanaka C, Yin OQ , Sethuraman V, et al. Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib. Clinical Pharmacology and Therapeutics. 2010;87:197-203
  130. 130. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clinical Cancer Research. 2008;14:352-359
  131. 131. Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, et al. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clinical Pharmacokinetics. 2005;44:1067-1081
  132. 132. Smith DA, Koch KM, Arya N, Bowen CJ, Herendeen JM, Beelen A. Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. British Journal of Clinical Pharmacology. 2009;67:421-426
  133. 133. Ko Y, Tan SLD, Chan A, Wong YP, Yong WP, Ng RCH, et al. Prevalence of the coprescription of clinically important interacting drug combinations involving oral anticancer agents in Singapore: A retrospective database study. Clinical Therapeutics. 2012;34:1696-1704
  134. 134. Chan A, Tan SH, Wong CM, Yap KYL, Ko Y. Clinically significant drug−drug interactions between oral anticancer agents and nonanticancer agents: A delphi survey of oncology pharmacists. Clinical Therapeutics. 2009;31:2379-2386
  135. 135. Teillet F, Boumendjel A, Boutonnat J, Ronot X. Flavonoids as RTK inhibitors and potential anticancer agents. Medicinal Research Reviews. 2008;28(5):715-745
  136. 136. Li C, Wang T, Zhang C, Xuan J, Su C, Wang Y. Quercetin attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Gene. 2016;577:275-280
  137. 137. Larsen CA, Dashwood RH, Bisson WH. Tea catechins as inhibitors of receptor tyrosine kinases: Mechanistic insights and human relevance. Pharmacological Research. 2010;62:457-464
  138. 138. Chandrika BB, Steephan M, Kumar TR, Sabu A, Haridas M. Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibitors. Life Sciences. 2016;160:47-56
  139. 139. Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ. Effect of St John's wort on imatinib mesylate pharmacokinetics. Clinical Pharmacology and Therapeutics. 2004;76:323-329
  140. 140. Smith PF, Bullock JM, Booker BM, Haas CE, Berenson CS, Jusko WJ. Induction of imatinib metabolism by hypericum perforatum. Blood. 2004;104:1229-1230
  141. 141. Wong SF. New dosing schedules of dasatinib for CML and adverse event management. Journal of Hematology & Oncology. 2009;2:10
  142. 142. Wang Z, Wang L, Xia MM, Sun W, Huang CK, Cui X, et al. Pharmacokinetics interaction between imatinib and genistein in rats. BioMed Research International. 2015;2015:368976
  143. 143. Wang L, Wang Z, Xia MM, Wang YY, Wang HY, Hu GX. Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro. Canadian Journal of Physiology and Pharmacology. 2014;92:961-964
  144. 144. Liu XY, Xu T, Li WS, Luo J, Geng PW, Wang L, et al. The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. BioMed Research International. 2013;2013:789184
  145. 145. Ge J, Tan BX, Chen Y, Yang L, Peng XC, Li HZ, et al. Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: Potential risk of diminished sunitinib bioavailability. Journal of Molecular Medicine (Berlin, Germany). 2011;89:595-602
  146. 146. Smith NF, Baker SD, Gonzalez FJ, Harris JW, Figg WD, Sparreboom A. Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100. British Journal of Cancer. 2008;98:1630-1632
  147. 147. Yin OQ , Gallagher N, Li A, Zhou W, Harrell R, Schran H. Effect of grapefruit juice on the pharmacokinetics of nilotinib in healthy participants. Journal of Clinical Pharmacology. 2010;50:188-194
  148. 148. Hwang SW, Han HS, Lim KY, Han JY. Drug interaction between complementary herbal medicines and gefitinb. Journal of Thoracic Oncology. 2008;3:942-943

Written By

Muzaffar Iqbal

Submitted: 21 October 2018 Reviewed: 04 May 2020 Published: 05 June 2020