Introductory Chapter: Pharmacokinetics and Drug Metabolism with Special Reference to Herbal Formulations

1. Introduction to herbal formulations

Plant-based treatments are crucial in achieving Sustainable Development Goal 3 (SDG 3) to ensure healthy lives and promote well-being. Integrating effective and safe herbal medical systems with traditional pharmaceutical systems can significantly enhance essential healthcare services. A survey conducted in Germany revealed that various age groups opt for herbal remedies due to dissatisfaction with allopathic treatments, the synergistic effects of medicinal plants, historical usage, and unique knowledge [1]. In the face of emerging diseases like SARS-COV-2 and mycosis, interest in phytotherapy has been rekindled to strengthen the healthcare system and combat the ongoing epidemic. Immunity-boosting plants, herbal remedies, and AYUSH compositions are being considered as preventive measures. Specific botanical formulations include the aqueous solution of Guduchi and pippali, AYUSH 64, and Guduchi aq. extracts have shown promise for mild to moderate and asymptomatic COVID-19 patients [2]. Ashwagandha and Guduchi extracts are also recommended for preventive use against COVID-19, with Withaferin A potentially acting as a therapeutic agent to inhibit viral spread. However, further research is needed to determine the long-term safety and optimal dosage [3]. Currently, herbal medicines straddle the line between conventional drugs and food. This chapter elucidates their historical significance, integration into modern healthcare, and metabolic and pharmacokinetic profiles within the human body.

1.1 Importance of understanding herbal formulations’ metabolism and pharmacokinetics

Researchers are increasingly curious about the impact of herbal formulations on metabolism and pharmacokinetics. Pharmacokinetics (PK), a newly developed approach, is instrumental in studying drug absorption, distribution, metabolism, and excretion in vivo. When combined with other techniques, PK helps determine the active components of medicinal plants [4, 5, 6]. Pharmacokinetic measures like biological half-life, clearance, and AUC reveal dynamic processes of these components in vivo. Contrasting pharmacokinetic parameters aids in understanding their characteristics [7, 8]. This has three benefits: precise explanation of herbal formulation effects by identifying components, clarifying interactions of active substances (Figure 1), and demonstrating dynamic actions of active ingredients in vivo (Figure 1). These discoveries support the clinical use and understanding of medicinal plants.

Figure 1.

Representation of pharmacokinetics studies of active constituents via in vivo. Cmax, maximum plasma concentration; MTC, minimum toxic concentration; Tmax, time to Cmax; AUC, area under curve; MEC, minimum effective concentration.

Researchers discovered how the active components in medicinal plants produce their therapeutic benefits by thoroughly examining them. For instance, artemisinin was employed as a malaria preventative. Rhein, geniposide, and 6,7-dimethylesculetin were successful treatments for hepatic damage syndrome. Nonbacterial prostatitis was treated with berberine. Additionally, research employing PK has helped us to better understand the dynamic mechanisms of the active components of medicinal plants in vivo [2, 3], shown in Figure 1.

2. Absorption, distribution, metabolism, and excretion (ADME) of herbal compounds

2.1 Absorption of herbal compounds in the gastrointestinal tract

The impact of oral herbal therapies on individuals and their influencing factors remains understudied. Oral absorption is critical for defining bioavailability of medicinal ingredients from plants. Research on oral absorption is primarily based on animal and cell studies (e.g., Caco-2 cells). Some herbal substances have been assessed for oral bioavailability values, influenced by factors such as gastric fluid solubility, membrane permeability, gastrointestinal tract deprivation, and transporters like P-glycoprotein (P-gp/MDR1/ABCB1). Low or weak intestinal absorption may lead to inadequate oral bioavailability of herbal ingredients, as seen with curcumin. To enhance bioavailability, various formulations like liposomes and nanotechnology-based approaches have been developed [9]. Further research is needed to optimize oral herbal therapies and maximize their therapeutic potential.

2.2 Distribution of herbal compounds in the body

The albumin from human serum (HSA), 1-acid glycoprotein (AGP), lipoprotein, or and globulin are examples of plasma proteins connected to the ADME and pharmacodynamics properties of drugs in the body through bidirectional interactions.

The hydrophobic cavity in HSA is crucial in explaining how it affects the distribution and efficacy of medications. The hydrophobic cavity in HSA can alter the distribution of cells in vivo and in vitro and increase the apparent dissolution of hydrophobic drugs in plasma.

Human serum albumin and berberine, a conventional herbal remedy used to treat gastrointestinal diseases, were examined by Hu et al. The findings showed that the hydrophobic pocket of subdomain IIA was where berberine bound most frequently and that electrostatic forces played a significant role in the interaction of berberine and HSA.

The blood–brain barrier (BBB), which blocks substances from circulating blood from entering the brain through paracellular and transcellular routes, comprises humans’ tightly connected brain endothelial cells. These multidrug transporters can prevent harmful circulatory chemicals, including herbal medicines, from making it to the brain. However, these transporters will impede and lessen the efficiency of herbal drugs that impact the central nervous system [10].

2.3 Metabolism of herbal compounds in the liver

The human gut is where herbal substances are subjected to CYP- and UGT-mediated metabolism, which may be a critical factor in influencing intake and bioavailability. Following oral ingestion, herbal essences are vulnerable to presystemic oxidative and/or coupling metabolism, and the presence of several CYPs (in particular CYP3A4), and UGTs is significant in the gut. When absorbing diverse herbal compounds from the core, intestinal CYP3A4 can act as a very effective metabolic barrier without the help of the liver.

Numerous herbal substances often undergo intestinal hydrolysis, yielding pharmacologically active or degraded metabolites. Many herbal treatments’ glycosides typically undergo intestinal deglycosylation before being absorbed, and phenolic compounds’ aglycones are then sulfated or glucuronidated in the gut and liver. Emodin and sennidin are broken down in the colon to create their pharmacologically effective aglycones [11].

2.4 Excretion of herbal compounds from the body

Herbal medicines taken orally undergo absorption, metabolism, and subsequent elimination through feces and/or kidneys. Most plant natural products have a short elimination half-life, and their parent chemicals or metabolites can be detected in urine and feces. Urinary excretion is the primary route for eliminating herbal medicine metabolites or parent chemicals, followed by biliary excretion, involving specific drug transporters. For instance, after intravenous administration of 100 mg quercetin, 7.4% was excreted in the urine as a conjugation metabolite, and 0.65% remained unchanged. Quercetin and kaempferol showed recovery rates of 99.7% and 97.4%, respectively. Many herbal medicines are also eliminated through biliary excretion, with fecal recovery rates varying depending on the compound administered [12, 13, 14, 15, 16]. The exact role of hepatic transporters in biliary elimination of herbal treatments remains uncertain.

3. Enzymes involved in the metabolism of herbal compounds

Enzymes play a crucial role in the metabolism of herbal compounds, impacting their absorption, distribution, and elimination within the body. Phase I enzymes, such as Cytochrome P450 (CYP) and Flavin-Containing Monooxygenases (FMO), initiate biotransformation reactions like oxidation, reduction, and hydrolysis. These reactions can either enhance or reduce the biological activity of herbal compounds. Phase II enzymes, like Glucuronosyltransferases, Sulfotransferases, and Glutathione S-Transferases, facilitate conjugation reactions, making herbal compounds more water-soluble for easier excretion [17]. The interplay between Phase I and Phase II enzymes influences the fate of herbal compounds, affecting their pharmacokinetics, efficacy, and potential interactions with other drugs. Understanding these enzyme-mediated processes is crucial for optimizing the therapeutic use of herbal formulations and ensuring patient safety.

3.1 Cytochrome P450 enzymes and herbal drug metabolism

Cytochrome P450 (CYP) enzymes are a group of heme-containing proteins primarily found in the liver and other tissues. They play a crucial role in metabolizing a diverse range of drugs, including herbal compounds. In the metabolism of herbal drugs, CYP enzymes are responsible for transforming the active constituents present in herbal formulations. This biotransformation involves various chemical reactions such as oxidation, hydroxylation, and dealkylation, leading to the formation of metabolites with different pharmacological properties than the original compounds [18]. Consequently, the activity of CYP enzymes can significantly impact the efficacy, safety, and potential interactions of herbal drugs with other medications. It is crucial for healthcare professionals and researchers to understand the role of CYP enzymes in herbal drug metabolism to optimize therapies and ensure patient safety when using herbal formulations in combination with conventional medicines.

3.2 Glucuronidation and other phase II enzymes

Glucuronidation is a significant Phase II biotransformation reaction responsible for metabolizing herbal compounds and other xenobiotics. UDP-glucuronosyltransferases (UGTs) are the enzymes involved in this process, transferring glucuronic acid from UDP-glucuronic acid to the functional groups of herbal compounds, increasing their hydrophilicity and facilitating their excretion from the body. Other important Phase II enzymes in herbal drug metabolism include sulfotransferases, methyltransferases, and glutathione S-transferases (GSTs). Sulfotransferases add sulfate groups, methyltransferases add methyl groups, and GSTs conjugate herbal compounds with glutathione, promoting detoxification and enhanced excretion. The interplay of Phase II enzymes complements Phase I reactions, ensuring efficient and safe herbal compound metabolism [19]. Understanding these enzymatic processes is crucial for optimizing herbal formulations’ use and promoting their safe integration into healthcare practices.

3.3 Transporters and their role in herbal drug interactions

Transporters are membrane proteins that play a crucial role in the absorption, distribution, and elimination of herbal compounds and other drugs in the body. Table 1 provides examples of herbal compounds and their interactions with transporters, illustrating the impact on the pharmacokinetics of co-administered drugs. The table likely includes information about specific herbal blends, their respective transporters, and their effects on the absorption, distribution, and elimination of other drugs. These examples showcase how herbal formulations can influence the activity of transporters, leading to altered drug bioavailability and potential herb-drug interactions [20]. Understanding such interactions is crucial for healthcare professionals to ensure the safe and effective use of herbal and conventional drugs. Integrating this knowledge into clinical practice can enhance patient outcomes and minimize the risk of adverse effect.

Enzymes	Examples	Function
Phase I enzymes	Cytochrome P450 (CYP) enzymes	Oxidation, Reduction, and Hydrolysis of herbal compounds into more water-soluble metabolites.
	Flavin-containing monooxygenases (FMOs)	Involved in the oxidation of nitrogen, sulfur, and phosphorous-containing compounds.
Phase II enzymes	UDP-glucuronosyltransferases (UGTs)	Conjugation of herbal compounds with glucuronic acid, increasing water solubility for excretion.
	Sulfotransferases (SULTs)	Conjugation of herbal compounds with sulfate, enhances their excretion.
	Glutathione S-transferases (GSTs)	Conjugation of herbal compounds with glutathione facilitates their elimination.
	N-Acetyltransferases (NATs)	Conjugation of herbal compounds with acetyl groups, promoting excretion.
Cytochrome P450 (CYP) enzymes	CYP3A4	Metabolizes a wide range of herbal compounds and drugs commonly involved in interactions.
	CYP2D6	Metabolizes several herbal compounds and drugs, and genetic polymorphisms may affect metabolism.
	CYP2C9	Metabolizes various herbal compounds and drugs, which is important in drug interactions.
Transporters	P-glycoprotein (P-gp)	Efflux transporter pumps herbal compounds out of cells, affecting absorption and distribution.
	Multidrug Resistance-Associated Proteins (MRPs)	Efflux transporters are involved in herbal compounds and drug elimination.
	Breast Cancer Resistance Protein (BCRP)	Efflux transporter limiting absorption and distribution of herbal compounds and drugs.
	Organic Anion Transporting Polypeptides (OATPs)	Uptake transporters facilitate herbal compound absorption into cells.
	Organic Cation Transporters (OCTs)	Uptake transporters involved in the cellular uptake of herbal compounds

Table 1.

The examples of enzymes, cytochrome P450 enzymes, and transporters involved in the metabolism and interactions of herbal compounds.

4. Factors affecting pharmacokinetics of herbal formulations

The Pharmacokinetics of herbal formulations is affected by chemical composition, the bioavailability of active compounds, formulation methods, and individual variability in metabolism, genetics, age, and health status. Drug interactions and co-administration with other substances also influence the pharmacokinetic profile, necessitating safe and effective clinical use consideration.

4.1 Herb-drug interactions and their impact on pharmacokinetics

Herb-drug interactions occur when herbal compounds interact with conventional medications, affecting their pharmacokinetics. These interactions can lead to altered drug absorption, distribution, metabolism, or excretion, potentially impacting therapeutic outcomes or causing adverse effects. Understanding and monitoring such interactions are crucial in clinical settings to ensure the safe and effective use of both herbal remedies and pharmaceutical drugs. Healthcare professionals must be vigilant in assessing and managing herb-drug interactions to optimize patient outcomes and safety [21].

4.2 Influence of genetics and individual variation on herbal drug metabolism

Genetics and individual variation play a crucial role in herbal drug metabolism. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters can lead to significant inter-individual differences in how herbal compounds are processed and eliminated from the body. Variations in these genes can affect the efficacy and safety of herbal formulations and contribute to herb-drug interactions. Pharmacogenomic studies help identify genetic factors influencing herbal drug metabolism, enabling personalized treatment approaches. Considering individual genetic variations is essential to optimize herbal therapy, minimize adverse reactions, and achieve desired therapeutic outcomes for each patient. Moreover, the Effect of Food and Dietary Components on Herbal Drug Absorption is preciously discussed in Table 2.

Dietary component	Effect on herbal drug absorption
High-fat foods	May increase the absorption of lipophilic herbal compounds.
High-fiber foods	Can delay the absorption of herbal drugs and reduce their bioavailability.
Grapefruit juice	Can inhibit the activity of certain drug-metabolizing enzymes, affecting drug absorption.
Alcohol	May enhance the absorption of some herbal compounds and alter drug metabolism.
Calcium-rich foods	Can interfere with the absorption of certain herbal drugs.
Caffeine	May enhance the absorption of certain herbal compounds.
Spices and Piperine	Piperine present in black pepper can increase the bioavailability of herbal drugs.
Probiotics	Can influence the gut microbiota and affect the metabolism of herbal compounds.
Iron-rich foods	May reduce the absorption of certain herbal drugs.

Table 2.

Effect of food and dietary components on herbal drug absorption [22, 23].

5. Conclusion

The chapter emphasizes the importance of understanding the dynamic processes by which herbal compounds are absorbed, distributed, metabolized, and excreted in the body. Researchers are increasingly exploring the impact of herbal formulations on metabolism and pharmacokinetics using pharmacokinetic (PK) studies. PK helps identify active components, elucidate the effects of herbal formulations, and understand their dynamic actions in vivo. Chemical composition, bioavailability, formulation methods, and individual variability in metabolism and genetics influence herbal drug metabolism. The chapter also discusses herb-drug interactions, the role of enzymes and transporters, and the effect of food and dietary components on herbal drug absorption. Understanding these processes is crucial for optimizing herbal therapies and ensuring safe and effective integration into healthcare practices.

Conflict of interest

The authors declare no conflict of interest.