Open access peer-reviewed chapter

Drug Metabolism: Phase I and Phase II Metabolic Pathways

Written By

Noor ul Amin Mohsin, Maryam Farrukh, Saba Shahzadi and Muhammad Irfan

Submitted: 31 July 2023 Reviewed: 08 August 2023 Published: 14 February 2024

DOI: 10.5772/intechopen.112854

From the Edited Volume

Drug Metabolism and Pharmacokinetics

Edited by Mithun Rudrapal

Chapter metrics overview

131 Chapter Downloads

View Full Metrics

Abstract

Drug metabolism comprises the metabolism of endogenous and exogenous substances. During metabolism most drugs lose the pharmacological activity and are excreted from the body. Drug metabolic reactions are divided into two classes i.e. phase I and phase II metabolic reactions. The characterisation of drug metabolising enzyme is necessary in order to determine the toxic metabolites of drugs. The understanding of drug metabolism is essential for new drug design and development. The evaluation of pharmacokinetic properties is necessary to see whether they can be useful drug candidates. In this chapter we have discussed drug metabolic reaction and drug metabolising enzymes with the help of examples of drug molecules.

Keywords

  • cytochrome p450
  • glucuronic acid
  • glutathione
  • prodrug
  • toxic metabolites
  • drug design

1. Introduction

The human body is exposed to various foreign particles that are dust particles, food, toxins, and air pollutants. These foreign particles are collectively called xenobiotics. The term xeno means foreign, which is not a part of our body normally. When these foreign particles enter the body, the body has a mechanism to modify these particles so that they are excreted from the body. This process is called metabolism. Drugs are also regarded as xenobiotics as drugs are foreign particles. The process of drug metabolism is also called biotransformation. Normally, the metabolism decreases pharmacological effect but sometimes metabolism produces toxic metabolites or active metabolites. Drugs which undergo metabolism to produce a pharmacological effect are called prodrugs. Some drugs undergo metabolism to produce toxic metabolites that are carcinogenic or mutagenic. The liver is the main site of metabolism in the body. Some drugs are metabolised before reaching the systemic circulation, this is called the first-pass effect. Drug metabolism also occurs in the kidney, skin and gastrointestinal tract (GIT) etc. There are two phases of drug metabolism i.e. phase I metabolic reactions and phase II metabolic reactions.

Advertisement

2. Phase I reaction

These are non-synthetic reactions that introduce a hydrophilic group or unmask the already present hydrophilic group in these drugs. Phase I reactions include oxidation, reduction and hydrolysis.

2.1 Oxidation

The process of oxidation is catalysed by a class of enzymes that are collectively called cytochrome P450 (Cyp-450). They are present in the smooth endoplasmic reticulum (SER) of the liver. These are also known as microsomal enzymes because they are present in the microsome of SER [1]. The Cyp-450 consists of a protoporphyrin ring (Figure 1) having four (4) pyrrole rings. Pyrrole is a five-membered heterocyclic ring which contains one nitrogen atom. In Cyp450, four pyrrole rings are linked by a methylene bridge and the nitrogen of each pyrrole ring are combined with iron. The iron is present in ferric form (Fe+3) and is also associated with the sulphur of cysteine which is the peptide part. It can form a complex with carbon monoxide (CO). The complex of ferric (Fe+3) with CO gives an absorption bond at 450 nm wavelength hence these enzymes are called CYP-450 [2].

Figure 1.

Porphyrin ring of cytochrome P450.

Various drugs undergo the process of oxidation. In oxidation, first of all, the drug is attached to CYP-450 to form a complex. The iron in CYP-450 is converted into a ferrous form. It gains an electron and this reaction is catalysed by CYP-450 reductase and functions with a co-enzyme that is nicotinamide adenine dinucleotide phosphate hydrogenase (NADPH) shifts an electron from co-enzyme to iron (CYP-P450). In the next step, molecular oxygen gets attached to the complex of the drug and CYP450. The oxygen attached to the complex is converted into activated oxygen by a series of steps. The iron loses an electron and is converted into a ferric form by CYP-450 reductase and NADPH. The molecular oxygen is converted into atomic oxygen in the process of oxidation. One atom of oxygen is converted into the water molecule and another atom of oxygen is incorporated into the xenobiotic. CYP-450 again comes in its original form and the drug molecule is oxidised. There are many types and subtypes of CYP450 but the most important are CYP1A2, CYP2C9, CYP2D6, CYP2A6, CYP2E1, and CYP3A4. This system is non-specific and catalyses the oxidation of a large number of drugs. Lipid soluble substances are excellent substrates of this system because these enzymes are located mainly in lipid tissues. The process of oxidation takes place at different functional groups and hetero atoms. For example, aromatic rings, the alkyl group and the amino group [3]. This process takes place in drugs which contain aromatic rings in their structures. The hydrophilic group is introduced in the aromatic ring. This mostly occurs at the para position via the formation of an epoxide intermediate. For example, the conversion of acetanilide into acetaminophen (Figure 2) is an example of aromatic hydroxylation.

Figure 2.

Conversion of acetanilide into acetaminophen.

Some drug molecules contain heteroatom in their structure and the process of oxidation takes place at the heteroatom. Sulphur heteroatoms are oxidised to sulfoxides (Figure 3) and sulfones. Secondary amines are converted into lactam. Flavin monooxygenase (FMO) catalyses oxidation in drugs that contain hetero atoms in their structure. In this case, first of all, activation of molecular oxygen takes place before the attachment of xenobiotics but in the CYP-450 enzyme, the first step involves the attachment of the drug and then activation of molecular oxygen. For example, the anticancer agent tamoxifen is converted into tamoxifen N-oxide by FMO [4].

Figure 3.

Oxidation of tamoxifen into tamoxifen N-oxide.

The alkyl groups are removed from the amino group by the process of oxidation. Tertiary amines are converted to secondary amines and secondary amines are converted to primary amines. The rate of N-dealkylation depends upon the chain length of the alkyl group [5]. Mephorbarbital has a tertiary amine and it is converted into phenobarbital which has a secondary amine (Figure 4). The methyl group is converted into formaldehyde. Primary amines are more water solubility than secondary and tertiary amines. Usually, drugs lose pharmacological activity after oxidation but phenobarbital retains its activity after oxidation. The n-dealkylation produces a pharmacologically active compound. The conversion of amitriptyline into nortriptyline is also an example of n-dealkylation.

Figure 4.

Examples of n-dealkylation.

Drugs molecules that contain a primary amino (NH2) group undergo oxidative deamination (Figure 5) in which the amino group is directly removed and oxygen is incorporated in drug molecules. Ammonia (NH3) is converted into uric acid that is excreted from the body via urine.

Figure 5.

Deamination of amphetamine into phenylpropanone.

Drug molecules having ether linkage in their structure undergo the process of oxidative dealkylation. An alkyl group is removed from oxygen in compounds that undergo oxidation dealkylation. For example, the conversion of phenacetin into acetaminophen (Figure 6).

Figure 6.

Oxidative dealkylation of phenacitin into acetaminophen.

The hydrophilic group (-OH) has been unmasked in acetaminophen at this site. Phenacetin has also analgesic and antipyretic activity but due to hepatotoxicity toxicity, it was withdrawn from the market. But it was proved that phenacetin is converted into acetaminophen in the body by oxidative dealkylation which is a safer drug than phenacetin.

2.2 Reduction

Drug molecules which contain reducible groups like nitro, azo, alkene, aldehydes, and ketones easily undergo the process of reduction. The process of reduction is catalysed by specific enzymes which catalyse the reduction for specific classes. The nitro reductase is required for the reduction of the nitro group. The azo reductase is required for the reduction of the azo group. Aldo-keto reductases are required for the reduction of aldehydes and ketones. Opiate antagonist naloxone is reduced in liver to naloxol. Chloral hydrate undergoes the process of reduction and is converted into trichloroethanol (Figure 7). These enzymes are mainly located in the liver but small quantities are present in lungs and kidney. The enzymes which carry out the process of reduction also require a co-enzyme NADPH (nicotinamide adenine dinucleotide phosphate hydrogenase) [6]. The reduction introduces a hydrophilic group in the drug molecule or unmasks the already present hydrophilic group. The metabolism of chloramphenicol is an example of nitro reduction. It is an antibiotic and a protein synthesis inhibitor. It contains the nitro (-NO2) group, reduction takes place in this group and it is converted into the amino (-NH2) group and the remaining structure is the same.

Figure 7.

Nitro and aldo reduction of chloramphenicol and chloral hydrate.

Certain drugs contain azo group in their structures, for example, prontosil. The azo group is reduced and converted into two fragments sulfanilamide and triaminobenzene (Figure 8). Sulfanilamide is a prototype sulphonamide used as an antibacterial agent. Azo reductases are present in the liver. Sulfasalazine is a sulfonamide derivative used in ulcerative colitis. It is a prodrug and carries azo linkage that reduces in the intestine to form sulfapyridine and p-amino salicylic acid. Sulfpyridine has antibacterial activity. This process of reduction is catalysed by bacteria present in the intestines (normal intestinal flora) which produce the enzyme [7].

Figure 8.

Azo reduction of prontosil and sulfasalazine.

2.3 Hydrolysis

The process of hydrolysis takes place in drug molecules which contain ester or amide linkage in their structure. Drug molecules like acetylcholine, suxamethonium, acetylsalicylic acid and procaine carry ester linkage in their scaffolds (Figure 9).

Figure 9.

Ester hydrolysis of aspirin and procaine.

Aspirin is an acid but also contains an ester group in its structure. The ester group is hydrolysed. Esterases and pseudocholinesterase are enzymes which catalyse the process of hydrolysis of the drugs-containing ester groups. Esterases are specific in its action but pseudocholinesterase is not specific in their action. Pseudocholinesterases have broad specificity and can catalyse various groups. The hydrolysis of amides is catalysed by amidases, and peptidases. Procaine is a local anaesthetic and also contains an ester linkage. When the ester group is hydrolysed, acid and alcohol are formed. Diethylamino ethanol and p-aminobenzoic acid are products of the hydrolysis of procaine. The hydroxyl group is highly hydrophilic so the drug undergoes the process of phase II metabolism readily. The hydrolysis of drugs containing the amide group is very slow while the hydrolysis of the ester group is faster [8]. Chloramphenicol has a bitter taste so combined with palmitic acid to produce chloramphenicol palmitate (Figure 10). This prodrug is in ester form and then after absorption in the systemic circulation, this ester form of chloramphenicol undergoes hydrolysis and releases an active drug that is chloramphenicol.

Figure 10.

Ester hydrolysis of chloramphenicol palmitate.

Therefore, esters are presented as prodrug form and amides can be presented as a slow-release drug.

Advertisement

3. Phase II metabolism

Phase II metabolic reactions represents the most important metabolic reaction and are called synthetic reactions. In phase II metabolic reactions, an endogenous molecule is attached to a drug molecule. Endogenous molecules are hydrophilic and increase the hydrophilicity of the drug. Phase II metabolic reactions decrease the affinity of the drug with the receptor and they are excreted from the body. The phase II reactions are collectively called conjugation reactions. Glucuronic acid conjugation, sulfate conjugation, amino acid conjugation, glutathione conjugation, acetylation, methylation are different types of phase II metabolic reactions. Phase II metabolic reactions are not substrate-specific. At one functional group, more than one conjugating enzymes can act. For example, the hydroxyl group can undergo glucuronic acid conjugation, sulfate conjugation and acetylation reactions. The amino group can be metabolised by glucuronic acid conjugation and acetylation.

3.1 Glucuronic acid conjugation

Glucuronic acid is an oxidation product of glucose and is a hydrophilic molecule. In this reaction, the molecule of glucuronic acid becomes attached to the drug molecule or any other xenobiotic (Figure 11). The hydrophilicity of the drug molecule increases. Before attachment, it is converted into an activated form/moiety which is uridine diphosphate glucuronic acid (UDPGA). Uridine is a combination of uracil and ribose sugar. When uridine is attached to the phosphate group, then it is called uridine diphosphate [9].

Figure 11.

Glucuronic acid conjugation of acetaminophen.

This reaction occurs at (-OH, NH2) hydrophilic site that is already introduced or unmarked during phase I reactions. The reaction is catalysed by uridine diphosphate glucuronosyltransferase (UGT) which is mainly present in liver and adjacent to CYP-450 in the endoplasmic reticulum (ER) of the liver. Drug molecules and activated form of glucuronic acid are present in the cytosol while UGT is present in SER so drug molecules and UDPGA are transferred to SER where glucuronic acid conjugation occurs and metabolite/conjugated product is transferred to the cytoplasm [10].

At physiological pH, the carboxylic (COOH) group of glucuronic acid becomes ionised. Then the whole conjugate molecule becomes ionised and this ionic form is excreted in the kidney by tubules. Some products of glucuronic acid conjugation are excreted into the bile. From the bile, they come into the intestine where enzyme glucuronidase is present which hydrolyses the conjugate and the active drug is reabsorbed from the small intestine into the systemic circulation and the process is called enterohepatic circulation [11].

The process of glucuronic acid conjugation usually terminates the pharmacological activity of drugs but in some cases drug is converted into an active form. For example, the conversion of morphine into morphine 6-glucuronide. Hydroxyl groups are attached at position 3 and 6 of morphine. When the conjugation occurs at position 6, a pharmacologically active metabolite is produced. Most of the drugs undergo glucuronic acid conjugation and it is the most important amongst phase II metabolic reactions. There is an abundant availability of glucose in the body. Glucuronic acid conjugation can also take place at amino group (-NH2) group. Examples are sulfonamides and desipramine.

3.2 Sulfate conjugation (SO4)

The process of sulfate conjugation takes place in drugs that contain hydrophilic groups such as hydroxyl and amino groups. Inorganic sulfate (SO4) ion is a hydrophilic group. In the process of conjugation, the SO4 becomes attached to drug molecules/xenobiotics but first of all, sulfate is converted into an activated form called 3-phosphoadenosine-5-phosphosulfate (PAPS) (Figure 12). The activated form of SO4 reacts with the drug molecule. Sulfotransferases are enzymes which catalyse the transfer of sulfate from PAPS to the xenobiotic molecule [12].

Figure 12.

Sulfate conjugation of acetaminophen.

Sulfate conjugation is catalysed by sulfotransferases and these enzymes are mostly present in the liver in the cytosol. Some sulfotransferases are also present in the Golgi apparatus. Sulfotransferases are also present in the intestine, brain and platelets of blood. Sulfate conjugation increases the hydrophilicity of drugs which are excreted from the body. Drugs which are metabolised by sulfate conjugation are endogenous steroids, catecholamines and other neurotransmitters. The pools of sulfate ions are limited in the body. Therefore, when a drug is administered for a longer time, then sulfate ions are depleted from the body. In this way, the process of glucuronic acid conjugation dominates [13].

3.3 Amino acid conjugation

The process of amino acid conjugation occurs in those drugs which contain carboxylic groups. For example, ibuprofen, ketoprofen and flurbiprofen. Glycine is the most important amino acid with which conjugation takes place but it also occurs with ornithine. In this reaction, there is the formation of a peptide bond between an amino acid and drug molecules. Amino acids are hydrophilic because they contain carboxylic and amino groups. First of all, drugs are converted into an activated form [14] (Figure 13). The carboxylic group of the drug reacts with ATP and the AMP ester of the drug is formed. Then co-enzyme A (CoSH) reacts with the AMP ester of the drug and the formation of the thioester is complete. In the third step, the amino acid glycine becomes attached to the drug molecule. The process of amino acid conjugation is catalysed by acyltransferase. The co-enzyme A regenerates at the end. Acyltransferase enzymes are located in the liver. By the attachment of glycine, the hydrophilicity of the drug increases and it is excreted from the body via kidney. Glycine conjugation also takes place at low doses but glucuronic acid conjugation dominates at large doses [3].

Figure 13.

Amino acid conjugation of xenobiotics.

3.4 Glutathione conjugation

Glutathione (GSH) is a molecule which contains three amino acids i.e. Cysteine, glycine and glutamic acid. The process of glutathione conjugation takes place in drugs having electrophilic centres. These centres are created by electron-withdrawing groups. Some anticancer agents undergo the process of glutathione conjugation. For example nitrogen mustards and nitrosoureas [15]. These drugs contain electron-withdrawing groups, they withdraw electrons, a positive charge is produced on the adjacent carbon atoms and it becomes electrophilic. Glutathione conjugation takes place between the drug and sulphhydryl group (SH) of glutathione (Figure 14). Glutathione ionises and hydrogen is removed from the SH group. A negative charge is developed on the sulphur atom. Glutathione conjugation does not require the activation of the endogenous molecule or substrate. This process is different from other conjugation reactions because glucuronic acid, sulfate and amino acid conjugations take place at nucleophilic centres. The glutathione conjugation is catalysed by glutathione-s-transferases located in the liver. Some glutathione conjugation reactions take place without the involvement of transferases. Most insecticides are metabolised by glutathione conjugation. Electron-withdrawing groups are also present in some insecticides and herbicides. Glutathione conjugation is the defensive mechanism of the body against toxic metabolites of foreign particles [16]. But glutathione is present in limited amounts in the body. If toxic compounds are ingested in large amount, the glutathione stores are depleted. In this situation, the body is exposed to the harmful effects of these metabolites. This conjugation reaction is a displacement or substitution reaction. When a drug is metabolised by glutathione conjugation it is not excreted from the body and it is further converted into mercapturic acid which is the end product. In this step, glutamic acid and glycine are cleaved from glutathione. Some scientists call it phase III metabolism [17].

Figure 14.

Glutathione conjugation of a xenobiotic.

3.5 Acetylation

The process of acetylation takes place in those drugs which contain amino group, hydrazine and hydrazide linkage in their structures. For example, sulfonamides and phenelzine etc. (Figure 15). In the process of acetylation, the amino group is converted into an amide group. The acetyl group is provided by acetyl co-enzyme A. The acetyl co-enzyme A is formed by pyruvic acid, the end product of glycolysis [18]. Generally, phase II reaction increase the hydrophilicity of drugs but the acetylation does not increase hydrophilicity. The process of acetylation terminates the activity of drugs. Acetyltransferase is the enzyme that transfers the acetyl group from acetyl coenzyme-A to drugs. These enzymes are mainly present in the liver but also in RBCs and lungs. Populations are divided into fast acetylators and slow acetylators. Slow acetylators are exposed to the toxic effects of drugs [19].

Figure 15.

Acetylation of drug molecules having amino group.

3.6 Methylation

Methylation is a process in which methyl group becomes attached to the drug molecule. The process of methylation mostly takes place in endogenous molecules. For example neurotransmitters, noradrenaline is converted into adrenaline by methylation (Figure 16). In most cases, methylation results in the formation of biologically active molecules. But in some cases it produces inactive metabolites.

Figure 16.

Methylation of neurotransmitters.

Methylation does not increase hydrophilicity because methyl group is lipophilic. Methyl group is provided by amino acid methionine. Methionine is converted into activated form which is called as S-adenosyl methionine. The process of methylation is catalysed by methyl transferases enzymes which are located in liver along with intestine and kidney [20]. There are three types of methylation i.e. N-methylation, O-methylation and S-methylation. Examples of N-methylation are conversion of noradrenaline into adrenaline, and histamine into n-methyl histamine. The conversion of tyrosine into methoxy tyrosine and dimercaprol into methylated form are examples of O-methylation and S-methylation respectively (Figure 17). There are specific enzymes for each reaction.

Figure 17.

Methylation of tyrosine and dimercaprol.

Advertisement

4. Drug metabolism and drug design

The knowledge of drug metabolism is important in new drug design and development. If the new drug is quickly metabolised in the body, some non-reactive groups are added which resist the drug metabolism. For example, tolbutamide (Figure 18) is an anti-diabetic drug and it has a shorter half-life (2.5 hrs). It undergoes the process of metabolism and the methyl group converted into a carboxyl group. If the methyl group is replaced by the chlorine atom, then this compound (chlorpropamide) achieves a longer half-life (12–15 hrs) as compared to tolbutamide [21]. Drug metabolism has a significant effect on pharmacokinetic, pharmacodynamic and safety of a drug [22]. Some drugs are administered in inactive forms and are called as prodrugs. In prodrug, a drug is chemically modified to overcome its problems of absorption, route of administration, metabolism and excretion. Prodrugs have labile functional groups which are easily metabolised in the body. For example, ester, phosphate, carbamate. Masking of polar functional improves oral bioavailability [23]. For example, chloramphenicol palmitate and bacampicillin are prodrugs of chloramphenicol and ampicillin respectively.

Figure 18.

Drug metabolism and drug design.

Advertisement

5. In silico pharmacokinetic studies

About 40% of new drugs fail in clinical trials because of poor pharmacokinetic properties. Nowadays pharmacokinetic properties of new compounds are evaluated by swissADME, ADMETlab and pkCSM web tools. 3D structure of compounds are generated on online software and pharmacokinetic properties ADMET (absorption, distribution, metabolism, excretion and toxicity) are computed. The GI absorption, BBB permeation, P-gp substrate, cytochrome P450 enzyme inhibition/induction, skin permeation are critical for the oral activity of drug molecules and these properties can be predicted. The prediction of pharmacokinetic properties helps to understand the behaviour of drug molecules in the human body. In silico predictions help to reduce the costly experimental approach [24]. The drug likeness of new molecules is also predicted by Lipinski rule of five [25]. According to this rule, drug molecules having more than five hydrogen bond donors, more than 10 hydrogen bond acceptor, logP more than five and molecular weight more 500 dalton are less likely to be orally active. High lipophilicity leads to the poor absorption of drug molecules. Similarly, compounds having big weights are less likely to absorb from GIT. About 80% drugs have molecular weight less than 450. The molecules having polar surface area less than 140°A and number of rotatable bond less than 10 also show good oral bioavailability. Drug molecules that follow the RO5 have increased chances of reaching the market and have less probability to fail during the clinical trials [26].

Advertisement

6. Conclusion

Drug metabolism is very significant in controlling the pharmacokinetics. Drug metabolising enzymes carry out the metabolism of endogenous as well as exogenous substances. Phase I metabolic reactions introduce a hydrophilic group in the drug molecules where phase II metabolic reactions can take place. In this chapter, we discussed the drug metabolic reactions and enzymes involved in these reactions. Most of the drugs are metabolised by CYP450 enzymes. The study of drug metabolism is essential for the safety and efficacy of drug molecules. The pharmacokinetic properties of drugs can be predicted by carrying out drug metabolism studies. The metabolic pathways of new drugs should be determined to predict the possibility of adverse drug reactions and drug-drug interactions.

References

  1. 1. Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nature Reviews Cancer. 2006;6(12):947-960
  2. 2. Foye WO. Foye’s Principles of Medicinal Chemistry. Philadelphia, USA: Lippincott Williams & Wilkins; 2008
  3. 3. Lakshmanan M. Drug metabolism. In: Introduction to Basics of Pharmacology and Toxicology. Vol. 12019. Singapore: Springer; 2019. pp. 99-116
  4. 4. Bortolussi S, Catucci G, Gilardi G, Sadeghi SJ. N-and S-oxygenation activity of truncated human flavin-containing monooxygenase 3 and its common polymorphic variants. Archives of Biochemistry Biophysics. 2021;697:108663
  5. 5. Eh-Haj BM. Metabolic N-dealkylation and N-oxidation as elucidators of the role of alkylamino moieties in drugs acting at various receptors. Molecules. 2021;26(7):1917
  6. 6. Marchitti SA, Brocker C, Stagos D, Vasiliou V. Non-P450 aldehyde oxidizing enzymes: The aldehyde dehydrogenase superfamily. Expert Opinion on Drug Metabolism Toxicology. 2008;4(6):697-720
  7. 7. Guo Y, Lee H, Jeong H. Gut microbiota in reductive drug metabolism. Progress in Molecular Biology Translational Science. 2020;171:61-93
  8. 8. Karaman R. Prodrugs design based on inter-and intramolecular chemical processes. Chemical Biology Drug Design. 2013;82(6):643-668
  9. 9. Ionescu C, Caira MR. Drug Metabolism: Current Concepts. Dordrecht: Springer; 2005
  10. 10. Ouzzine M, Gulberti S, Ramalanjaona N, Magdalou J, Fournel-Gigleux S. The UDP-glucuronosyltransferases of the blood-brain barrier: Their role in drug metabolism and detoxication. Frontiers in Cellular Neuroscience. 2014;8:349
  11. 11. Okour M, Brundage RC. Modeling enterohepatic circulation. Current Pharmacology Reports. 2017;3:301-313
  12. 12. Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The role of uptake and efflux transporters in the disposition of glucuronide and sulfate conjugates. Frontiers in Pharmacology. 2022;12:802539
  13. 13. Xie Y, Xie W. The role of sulfotransferases in liver diseases. Drug Metabolism Disposition. 2020;48(9):742-749
  14. 14. Hou Y, Hu S, Li X, He W, Wu G. Amino acid metabolism in the liver: Nutritional and physiological significance. In: Amino Acids in Nutrition Health: Amino Acids in Systems Function Health. Cham: Springer; 2020. pp. 21-37
  15. 15. Desideri E, Ciccarone F, Ciriolo MR. Targeting glutathione metabolism: Partner in crime in anticancer therapy. Nutrients. 2019;11(8):1926
  16. 16. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annual Review of Pharmacology & Toxicology. 2005;45:51-88
  17. 17. Hanna PE, Anders M. The mercapturic acid pathway. Critical Reviews in Toxicology. 2019;49(10):819-929
  18. 18. Liu Y, Bai C. Engineered ethanol-driven biosynthetic system for improving production of acetyl-CoA derived drugs in Crabtree-negative yeast. Metabolic Engineering. 2019;54:275-284
  19. 19. Hein DW, Millner LM. Arylamine N-acetyltransferase acetylation polymorphisms: Paradigm for pharmacogenomic-guided therapy-A focused review. Expert Opinion on Drug Metabolism Toxicology. 2021;17(1):9-21
  20. 20. Walvekar AS, Laxman S. Methionine at the heart of anabolism and signaling: Perspectives from budding yeast. Frontiers in Microbiology. 2019;10:2624
  21. 21. Kumar GN, Surapaneni S. Role of drug metabolism in drug discovery and development. Medicinal Research Reviews. 2001;21(5):397-411
  22. 22. Li Y, Meng Q , Yang M, et al. Current trends in drug metabolism and pharmacokinetics. Acta Pharmaceutica Sinica B. 2019;9(6):1113-1144
  23. 23. Doss GA, Baillie TA. Addressing metabolic activation as an integral component of drug design. Drug Metabolism Reviews. 2006;38(4):641-649
  24. 24. Alqahtani S. In silico ADME-Tox modeling: Progress and prospects. Expert Opinion on Drug Metabolism Toxicology. 2017;13(11):1147-1158
  25. 25. Lipinski CA. Lead-and drug-like compounds: The rule-of-five revolution. Drug Discovery Today: Technologies. 2004;1(4):337-341
  26. 26. Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews Drug Discovery. 2007;6(11):881-890

Written By

Noor ul Amin Mohsin, Maryam Farrukh, Saba Shahzadi and Muhammad Irfan

Submitted: 31 July 2023 Reviewed: 08 August 2023 Published: 14 February 2024