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Drug metabolism

From EverybodyWiki Bios & Wiki

This article is about the scientific concept of drug metabolism. For alternative medicine, see Detoxification (alternative medicine).


Drug metabolism is the metabolic breakdown and biotransformation of drugs by living organisms, usually through specialized enzymatic systems. It is a major aspect of pharmacokinetics and clinical pharmacology, influencing the duration, intensity, and elimination of pharmaceutical compounds, as well as drug interactions, prodrug activation, and interindividual variation in drug response.[1]

Drug metabolism is a specialized subset of xenobiotic metabolism, the broader set of biochemical pathways that modify foreign compounds such as drugs, toxins, and pollutants.[2] Most drug metabolism occurs in the liver through Phase I and Phase II enzymatic reactions, particularly those involving cytochrome P450 enzymes, which generally convert lipophilic compounds into more readily excreted hydrophilic metabolites.[3]

Permeability barriers and drug detoxification

Many pharmaceutical drugs are lipophilic compounds that diffuse across cell membranes and enter cells without requiring specific transport proteins. This property is important for drug absorption and distribution, but it also means that organisms cannot completely prevent exposure to membrane-permeable drugs and other foreign compounds. As a result, drug metabolism systems evolved to chemically modify and eliminate a wide range of structurally diverse compounds.[4]

Cell membranes act as hydrophobic permeability barriers that restrict the passive diffusion of most hydrophilic molecules. The uptake of endogenous metabolites and many therapeutic agents is therefore mediated by selective transport systems.[5] In contrast, many hydrophobic drugs can readily cross biological membranes and therefore require enzymatic conversion into more polar metabolites that can be excreted through urine or bile.

Drug-metabolizing enzymes consequently display broad substrate specificities and are capable of acting on many chemically unrelated compounds.[4] In humans, these systems are concentrated primarily in the liver and include enzymes such as the cytochrome P450 oxidases, which catalyse reactions that increase the polarity of drugs and facilitate their elimination.

In addition to metabolizing xenobiotic drugs, cells also contain specialized systems that detoxify reactive by-products generated during normal metabolism. Examples include the glyoxalase system, which removes the reactive aldehyde methylglyoxal,[6] and antioxidant systems that eliminate reactive oxygen species.[7]

Phases of drug metabolism

Main article: Xenobiotic metabolism § Phases of detoxification
File:Xenobiotic metabolism.png
Phase I and Phase II metabolism of a lipophilic drug.

Drug metabolism is commonly divided into three phases: modification (Phase I), conjugation (Phase II), and excretion (Phase III). These reactions generally convert lipophilic drugs into more hydrophilic metabolites that can be more readily eliminated from the body.

Phase I – modification

Phase I reactions introduce or expose reactive functional groups on drugs through oxidation, reduction, or hydrolysis. These reactions are catalyzed primarily by cytochrome P450 enzymes in the liver.[8]

A common Phase I reaction is hydroxylation, which increases drug polarity and facilitates excretion. Phase I metabolism may also activate prodrugs or generate pharmacologically active or toxic metabolites.[8]

Important Phase I enzymes include:

Phase II – conjugation

In Phase II reactions, drugs or Phase I metabolites are conjugated to endogenous polar molecules such as glucuronic acid, sulfate, glutathione, or glycine. These reactions generally increase water solubility and reduce pharmacological activity, thereby promoting elimination.[4]

Major Phase II pathways include:

These reactions are clinically important because variation in conjugating enzymes can influence drug clearance, efficacy, and toxicity.[9]

Phase III – transport and excretion

In Phase III, drug metabolites are exported from cells by membrane transporters such as members of the ATP-binding cassette transporter family, including multidrug resistance proteins (MRPs).[10][11]

These transport systems contribute to drug elimination through urine or bile, and can also influence multidrug resistance in cancer chemotherapy and infectious diseases.[12]

Sites

Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is taken into the gastrointestinal tract (GI tract), where it enters the hepatic portal system through the portal vein, it becomes well-metabolized and is said to show the first pass effect.

Other sites of extrahepatic drug metabolism include epithelial cells of the GI tract, lungs, kidneys, and skin. These sites are usually responsible for localized toxicity reactions.

Factors affecting drug metabolism

The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system (CYP) is a crucial pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true, as in enzyme inhibition. However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can accelerate this conversion and increase drug levels, potentially causing toxicity.[medical citation needed] For example, chemotherapy prodrugs like cyclophosphamide (CPA) and ifosfamide (Ifex), which are initially inactive, become toxic as they are metabolized into cytotoxic compounds (such as phosphoramide mustard and chloroacetaldehyde) primarily from liver enzymes CYP2B6[13] and CYP3A4. Co-administration of a strong CYP inducer, such as phenytoin or rifampicin, accelerates metabolism and increases the rate of bioactivation which causes a higher concentration of cytotoxic metabolites that may lead to higher toxicity. This drug–drug interaction may enhance the risk of adverse effects, most notably severe myelosuppression and hemorrhagic cystitis.[14][15][16]

Typically, drug-drug interactions are formally quantified by comparing the observed combined effect of two co-administered drugs against a theoretical baseline of no interaction. This concept, commonly referred to as the additive effect, explains the synergistic interaction, or lack thereof, between drugs. In order to validly quantify the effect, two primary null models are used: loewe additivity and bliss independence.[17] Loewe additivity (dosage additivity) postulates that if two drugs share the same mechanism of action, their combined effects should be identical to the effect achieved from taking a higher dose of either drug alone.[18] Bliss independence (response additivity) postulates that if two drugs act independently of each other, their combined effect should be the product of their individual effects. Both models identify two combined effects that signal a true drug interaction, as they deviate from the additive baseline: a synergistic effect, where the observed combined effect is greater than predicted which results in higher efficacy or toxicity levels; and an antagonistic effect, where the observed combined effect is less than predicted which often results in drug therapy problems.[18][19]

The therapeutic index (TI) of a drug is the measurement of its efficacy, calculated as the ratio of the median toxic dose (TD50) to the median effective dose (ED50).[20] Various Cytochrome P450 metabolic enzymes are inhibited or induced by many drugs. For example, chronic alcohol consumption will induce Cytochrome P450 enzymes, like CYP2E1, which enhances the metabolism of ethanol.[21] As a consequence, the induction of CYP2E1 will increase a person's tolerance levels and reduce the toxicity of ethanol. Additionally, CYP2E1 is involved with the metabolism of acetaldehyde (CH₃CHO), a metabolite of alcohol that is highly reactive and toxic, which can contribute to an alcohol-induced liver injury along with overoxidation.[22]

Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, sex differences or gut microbiota.[23] This last factor has significance because gut microorganisms are able to chemically modify the structure of drugs through degradation and biotransformation processes, thus altering the activity and toxicity of drugs. These processes can decrease the efficacy of drugs, as is the case of digoxin in the presence of Eggerthella lenta (E. lenta) in the microbiota.[24] Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs.[24] An example of polymorphism affecting drug metabolism is the alcohol flush reaction caused by the ALDH2 genetic mutation. The ALDH2 genetic mutation is prevalent among east Asians and causes a reduced activity of aldehyde dehydrogenase (ALDH), which assists in breaking down acetaldehyde (CH₃CHO).[25][26] As of 2019, approximately 560 million people (8% of the world's population in 2019) had this genetic mutation, which posed various health risks like metabolic disorders or an increased cancer risk.[27]

In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults. Inherited genetic variations in drug-metabolizing enzymes result in different catalytic activity levels. For example, N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly (rapid acetylators), split roughly 50:50 in the population of Canada. However, variability in NAT2 alleles distribution across different populations is high, and some ethnicities have a higher proportion of slow acetylators.[28] This variation in metabolizing capacity may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. NAT2 enzyme is a primary metabolizer of antituberculosis (isoniazid), some antihypertensive (hydralazine), anti-arrhythmic drugs (procainamide), antidepressants (phenelzine) and many more [29] and increased toxicity as well as drug adverse reactions in slow acetylators have been widely reported. Similar phenomena of altered metabolism due to inherited variations have been described for other drug-metabolizing enzymes, like CYP2D6, CYP3A4, DPYD, UGT1A1. DPYD and UGT1A1 genotyping is now required before administration of the corresponding substrate compounds (5-FU and capecitabine for DPYD and irinotecan for UGT1A1) to determine the activity of DPYD and UGT1A1 enzyme and reduce the dose of the drug in order to avoid severe adverse reactions.[30]

Dose, frequency, route of administration, tissue distribution, and protein binding of the drug affect its metabolism.[31]

Pathological factors can also influence drug metabolism, including liver, kidney, or heart disease.[32][33][34]

In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.[35] This can be used to identify individuals most at risk from adverse reaction.

History

Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as benzaldehyde could be oxidized and conjugated to amino acids in the human body.[36] During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation, acetylation, and sulfonation.

In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by Richard Williams of the book Detoxication mechanisms in 1947.[37] This modern biochemical research resulted in the identification of glutathione S-transferases in 1961,[38] followed by the discovery of cytochrome P450s in 1962,[39] and the realization of their central role in xenobiotic metabolism in 1963.[40][41]

See also

References

  1. ↑ Doogue MP, Polasek TM (February 2013). "The ABCD of clinical pharmacokinetics". Therapeutic Advances in Drug Safety. 4 (1): 5–7. doi:10.1177/2042098612469335. PMC 4110820. PMID 25083246.
  2. ↑ Surendradoss J, Varghese A, Deb S (2022-11-03). "Drug Metabolism: Detoxification and Xenobiotic Biotransformation". Biologically Active Small Molecules (1 ed.). New York: Apple Academic Press. pp. 287–332. doi:10.1201/9781003283119-17. ISBN 978-1-003-28311-9. Search this book on
  3. ↑ Surendradoss J, Varghese A, Deb S (2022-11-03). "Drug Metabolism: Detoxification and Xenobiotic Biotransformation". Biologically Active Small Molecules (1 ed.). New York: Apple Academic Press. pp. 287–332. doi:10.1201/9781003283119-17. ISBN 978-1-003-28311-9. Search this book on
  4. ↑ 4.0 4.1 4.2 Jakoby WB, Ziegler DM (December 1990). "The enzymes of detoxication". The Journal of Biological Chemistry. 265 (34): 20715–20718. Bibcode:1990JBiCh.26520715J. doi:10.1016/S0021-9258(17)45272-0. PMID 2249981.
  5. ↑ Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y (September 2003). "Impact of drug transporter studies on drug discovery and development". Pharmacological Reviews. 55 (3): 425–461. doi:10.1124/pr.55.3.1. PMID 12869659. Unknown parameter |s2cid= ignored (help)
  6. ↑ Thornalley PJ (July 1990). "The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life". The Biochemical Journal. 269 (1): 1–11. doi:10.1042/bj2690001. PMC 1131522. PMID 2198020.
  7. ↑ Sies H (March 1997). "Oxidative stress: oxidants and antioxidants". Experimental Physiology. 82 (2): 291–295. doi:10.1113/expphysiol.1997.sp004024. PMID 9129943.
  8. ↑ 8.0 8.1 Guengerich FP (June 2001). "Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity". Chemical Research in Toxicology. 14 (6): 611–650. doi:10.1021/tx0002583. PMID 11409933.
  9. ↑ Liston HL, Markowitz JS, DeVane CL (October 2001). "Drug glucuronidation in clinical psychopharmacology". Journal of Clinical Psychopharmacology. 21 (5): 500–515. doi:10.1097/00004714-200110000-00008. PMID 11593076. Unknown parameter |s2cid= ignored (help)
  10. ↑ Homolya L, Váradi A, Sarkadi B (2003). "Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate". BioFactors. 17 (1–4): 103–114. doi:10.1002/biof.5520170111. PMID 12897433. Unknown parameter |s2cid= ignored (help)
  11. ↑ König J, Nies AT, Cui Y, Leier I, Keppler D (December 1999). "Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance". Biochimica et Biophysica Acta. 1461 (2): 377–394. doi:10.1016/S0005-2736(99)00169-8. PMID 10581368.
  12. ↑ Commandeur JN, Stijntjes GJ, Vermeulen NP (June 1995). "Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics". Pharmacological Reviews. 47 (2): 271–330. doi:10.1016/S0031-6997(25)06846-2. PMID 7568330.
  13. ↑ El-Serafi I, Steele S (2024). "Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics". Advances in Pharmacological and Pharmaceutical Sciences. 2024 (1). doi:10.1155/2024/4862706. PMC 11223907 Check |pmc= value (help). PMID 38966316 Check |pmid= value (help). Unknown parameter |article-number= ignored (help)
  14. ↑ Gangireddy M, Patel P, Nookala V (2025). "Ifosfamide". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 31194326. Retrieved 2025-10-14. Search this book on
  15. ↑ Ogino MH, Tadi P (2025). "Cyclophosphamide". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 31971727. Retrieved 2025-10-14. Search this book on
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  17. ↑ Niu J, Straubinger RM, Mager DE (June 2019). "Pharmacodynamic Drug-Drug Interactions". Clinical Pharmacology and Therapeutics. 105 (6): 1395–1406. doi:10.1002/cpt.1434. PMC 6529235 Check |pmc= value (help). PMID 30912119.
  18. ↑ 18.0 18.1 Russ D, Kishony R (December 2018). "Additivity of inhibitory effects in multidrug combinations". Nature Microbiology. 3 (12): 1339–1345. doi:10.1038/s41564-018-0252-1. PMC 6295580. PMID 30323252.
  19. ↑ Yin N, Ma W, Pei J, Ouyang Q, Tang C, Lai L (2014). Aloy P, ed. "Synergistic and antagonistic drug combinations depend on network topology". PloS One. 9 (4). Bibcode:2014PLoSO...993960Y. doi:10.1371/journal.pone.0093960. PMC 3979733. PMID 24713621. Unknown parameter |article-number= ignored (help)
  20. ↑ "Therapeutic index | Pharmacology Education Project". www.pharmacologyeducation.org. Retrieved 2025-07-31.
  21. ↑ Heit C, Dong H, Chen Y, Thompson DC, Deitrich RA, Vasiliou VK (2013). "The Role of CYP2E1 in Alcohol Metabolism and Sensitivity in the Central Nervous System". Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism. Subcellular Biochemistry. 67. pp. 235–247. doi:10.1007/978-94-007-5881-0_8. ISBN 978-94-007-5880-3. ISSN 0306-0225. PMC 4314297. PMID 23400924. Search this book on
  22. ↑ Oneta CM, Lieber CS, Li J, Rüttimann S, Schmid B, Lattmann J, Rosman AS, Seitz HK (January 2002). "Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase". Journal of Hepatology. 36 (1): 47–52. doi:10.1016/S0168-8278(01)00223-9. PMID 11804663.
  23. ↑ Wilson ID, Nicholson JK (January 2017). "Gut microbiome interactions with drug metabolism, efficacy, and toxicity". Translational Research. 179: 204–222. doi:10.1016/j.trsl.2016.08.002. PMC 5718288. PMID 27591027.
  24. ↑ 24.0 24.1 Heinken A, Hertel J, Acharya G, Ravcheev DA, Nyga M, Okpala OE, Hogan M, Magnúsdóttir S, Martinelli F, Nap B, Preciat G, Edirisinghe JN, Henry CS, Fleming RM, Thiele I (19 January 2023). "Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine". Nature Biotechnology. 41 (9): 1320–1331. doi:10.1038/s41587-022-01628-0. PMC 10497413 Check |pmc= value (help). PMID 36658342 Check |pmid= value (help).
  25. ↑ Chang YC, Lee HL, Yang W, Hsieh ML, Liu CC, Lee TY, Huang JY, Nong JY, Li FA, Chuang HL, Ding ZZ, Su WL, Chueh LY, Tsai YT, Chen CH, Mochly-Rosen D, Chuang LM (September 2023). "A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators". Nature Communications. 14 (1): 5971. Bibcode:2023NatCo..14.5971C. doi:10.1038/s41467-023-41570-6. PMC 10520061 Check |pmc= value (help). PMID 37749090 Check |pmid= value (help).
  26. ↑ Z A, A B (2024-01-20). "Aldehyde Dehydrogenase 2 Deficiency and Associated Health Risks in East Asian Populations: An Overview". Journal of Chemical Health Risks. 14 (1): 824–840. doi:10.52783/jchr.v14.i01.2407 (inactive 9 February 2026). ISSN 2251-6727.
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  28. ↑ Gutiérrez-Virgen JE, Piña-Pozas M, Hernández-Tobías EA, Taja-Chayeb L, López-González ML, Meraz-Ríos MA, Gómez R (2023). "NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review". PloS One. 18 (4). Bibcode:2023PLoSO..1883726G. doi:10.1371/journal.pone.0283726. PMC 10079069 Check |pmc= value (help). PMID 37023111 Check |pmid= value (help). Unknown parameter |article-number= ignored (help)
  29. ↑ Fukunaga K, Kato K, Okusaka T, Saito T, Ikeda M, Yoshida T, Zembutsu H, Iwata N, Mushiroda T (2021). "Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity". Frontiers in Genetics. 12. doi:10.3389/fgene.2021.652704. PMC 8012690 Check |pmc= value (help). PMID 33815485 Check |pmid= value (help). Unknown parameter |article-number= ignored (help)
  30. ↑ Muldoon M, Beck M, Sebree N, Yoder R, Ritter S, Allen JD, Alqahtani Z, Grund J, Philips B, Hesse K, El Rouby N (February 2024). "Real-world implementation of DPYD and UGT1A1 pharmacogenetic testing in a community-based cancer center". Clinical and Translational Science. 17 (2). doi:10.1111/cts.13704. ISSN 1752-8054. PMC 10818131 Check |pmc= value (help). Unknown parameter |article-number= ignored (help)
  31. ↑ Ernstmeyer K, Christman E, eds. (2023). "Chapter 1 Pharmacokinetics & Pharmacodynamics". Nursing Pharmacology [Internet] (2nd ed.). Eau Claire (WI): Chippewa Valley Technical College. Search this book on
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  34. ↑ Gandhi A, Moorthy B, Ghose R (November 2012). "Drug disposition in pathophysiological conditions". Current Drug Metabolism. 13 (9): 1327–1344. doi:10.2174/138920012803341302. PMC 3937312. PMID 22746301.
  35. ↑ Rostami-Hodjegan A, Tucker GT (February 2007). "Simulation and prediction of in vivo drug metabolism in human populations from in vitro data". Nature Reviews. Drug Discovery. 6 (2): 140–148. Bibcode:2007NRvDD...6..140R. doi:10.1038/nrd2173. PMID 17268485. Unknown parameter |s2cid= ignored (help)
  36. ↑ Murphy PJ (June 2001). "Xenobiotic metabolism: a look from the past to the future". Drug Metabolism and Disposition. 29 (6): 779–780. PMID 11353742. Archived from the original on 2009-06-21. Unknown parameter |url-status= ignored (help)
  37. ↑ Neuberger A, Smith RL (1983). "Richard Tecwyn Williams: the man, his work, his impact". Drug Metabolism Reviews. 14 (3): 559–607. doi:10.3109/03602538308991399. PMID 6347595.
  38. ↑ Booth J, Boyland E, Sims P (June 1961). "An enzyme from rat liver catalysing conjugations with glutathione". The Biochemical Journal. 79 (3): 516–524. doi:10.1042/bj0790516. PMC 1205680. PMID 16748905.
  39. ↑ Omura T, Sato R (April 1962). "A new cytochrome in liver microsomes". The Journal of Biological Chemistry. 237 (4): 1375–1376. doi:10.1016/S0021-9258(18)60338-2. PMID 14482007.
  40. ↑ Estabrook RW (December 2003). "A passion for P450s (rememberances of the early history of research on cytochrome P450)". Drug Metabolism and Disposition. 31 (12): 1461–1473. doi:10.1124/dmd.31.12.1461. PMID 14625342.
  41. ↑ Estabrook RW, Cooper DY, Rosenthal O (1963). "The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex". Biochemische Zeitschrift. 338: 741–755. PMID 14087340.

Further reading

External links

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