[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Pharmacology](https://durgical.com/en/pharmacology/) › Drug metabolism and cytochrome P450 [Pharmacology](https://durgical.com/en/pharmacology/) · Topic # Drug metabolism and cytochrome P450 How the liver and gut chemically change drugs, why some drugs speed up or slow down others, and how prodrugs need to be switched on. Updated 2026-11-01 Drug metabolism turns fat-soluble molecules into forms the body can excrete. It happens mostly in the liver and gut wall, in two broad steps. The cytochrome P450 (CYP) enzymes do much of the first step, and they are where many drug interactions and genetic differences in response begin. ## Key points - Phase I (oxidation, reduction, hydrolysis) adds or exposes a reactive group; CYP enzymes do most oxidations. - Phase II (conjugation) attaches a large polar group: glucuronide, sulfate, acetyl, glutathione or methyl. - A few CYP enzymes handle most drugs: CYP3A4/5, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. - Inhibitors raise the levels of drugs that depend on that enzyme; inducers lower them. Inhibition acts within days, induction builds up over days to weeks. - Prodrugs need metabolism to become active: clopidogrel (CYP2C19), codeine (CYP2D6), enalapril (to enalaprilat). ## Phase I and phase II Metabolites are usually less active and more water-soluble, but not always: some are active (morphine from codeine), some are toxic (the reactive paracetamol metabolite normally neutralised by glutathione), and some are the real drug (prodrugs). Phase II conjugates are generally inactive and leave in urine or bile. - Phase I: oxidation (CYP, flavin monooxygenases), reduction, hydrolysis (esterases) - Phase II: glucuronidation (UGT), sulfation, acetylation (NAT2), glutathione conjugation, methylation (TPMT) ## The main CYP enzymes, with examples - CYP3A4/5: the largest share of drugs, in the liver and the gut wall; simvastatin, atorvastatin, many calcium channel blockers, ciclosporin - CYP2D6: codeine and tramadol (activation), many antidepressants and beta blockers such as metoprolol - CYP2C9: S-warfarin, phenytoin, many NSAIDs - CYP2C19: clopidogrel (activation), omeprazole and other PPIs - CYP1A2: theophylline, tizanidine, caffeine ## Inhibition and induction An inhibitor competes for or blocks the enzyme, so the substrate accumulates; an inducer increases enzyme production, so the substrate is cleared faster and may stop working. Induction also wears off slowly after the inducer is stopped, so levels of the other drug can rise later. - Strong CYP3A inhibitors: clarithromycin, itraconazole, ketoconazole, ritonavir; grapefruit juice acts mainly on intestinal CYP3A4 - Strong CYP2D6 inhibitors: fluoxetine, paroxetine - CYP1A2 inhibitors: ciprofloxacin, fluvoxamine - Strong inducers: rifampicin, carbamazepine, phenytoin, St John's wort ## Prodrugs and clinical consequences When the drug is a prodrug, inhibiting or lacking the activating enzyme reduces the effect instead of increasing it. The clopidogrel label warns that people with two loss-of-function CYP2C19 alleles form less active metabolite, and advises avoiding omeprazole or esomeprazole because they reduce its antiplatelet effect. For warfarin, CYP inhibitors can raise the INR and inducers can lower it. ## Memory aid Inhibitor: the drug piles up. Inducer: the drug runs out. Prodrug: flip both. ## Test yourself Think of the answer, then tap the question to see it. ## What is the main difference between phase I and phase II metabolism? Phase I adds or exposes a reactive group (oxidation, reduction, hydrolysis); phase II attaches a large polar molecule such as glucuronide, making excretion easier. ## Why does rifampicin often lower the effect of other drugs, and why is the onset gradual? It is a strong inducer: it increases the amount of CYP enzyme, which takes time to build up, so other substrates are cleared faster over days to weeks. ## Why do omeprazole and esomeprazole reduce the effect of clopidogrel? Clopidogrel is a prodrug activated mainly by CYP2C19; these PPIs inhibit CYP2C19, so less active metabolite forms. ## Which CYP enzyme metabolises the more potent form of warfarin? CYP2C9 metabolises S-warfarin, so CYP2C9 inhibitors or reduced-function variants can raise the INR. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/pharmacology/topics/drug-metabolism-and-cytochrome-p450/) ## Related classes - [Statins](https://durgical.com/en/pharmacology/classes/statins/) - [Vitamin K antagonists](https://durgical.com/en/pharmacology/classes/vitamin-k-antagonists/) - [Antiplatelet drugs](https://durgical.com/en/pharmacology/classes/antiplatelet-drugs/) - [Proton pump inhibitors (PPIs)](https://durgical.com/en/pharmacology/classes/proton-pump-inhibitors/) - [Opioids and antagonists](https://durgical.com/en/pharmacology/classes/opioids-and-antagonists/) ## Example drugs - [Warfarin](https://durgical.com/en/pharmacology/warfarin/) - [Clopidogrel](https://durgical.com/en/pharmacology/clopidogrel/) - [Omeprazole](https://durgical.com/en/pharmacology/omeprazole/) - [Simvastatin](https://durgical.com/en/pharmacology/simvastatin/) - [Atorvastatin](https://durgical.com/en/pharmacology/atorvastatin/) - [Codeine](https://durgical.com/en/pharmacology/codeine/) - [Rifampicin](https://durgical.com/en/pharmacology/rifampicin/) - [Carbamazepine](https://durgical.com/en/pharmacology/carbamazepine/) - [Phenytoin](https://durgical.com/en/pharmacology/phenytoin/) - [Clarithromycin](https://durgical.com/en/pharmacology/clarithromycin/) - [Itraconazole](https://durgical.com/en/pharmacology/itraconazole/) - [Ketoconazole](https://durgical.com/en/pharmacology/ketoconazole/) - [Ritonavir](https://durgical.com/en/pharmacology/ritonavir/) - [Fluoxetine](https://durgical.com/en/pharmacology/fluoxetine/) - [Paroxetine](https://durgical.com/en/pharmacology/paroxetine/) - [Enalapril](https://durgical.com/en/pharmacology/enalapril/) - [Sulfasalazine](https://durgical.com/en/pharmacology/sulfasalazine/) - [Paracetamol](https://durgical.com/en/pharmacology/paracetamol/) [← All of pharmacology](https://durgical.com/en/pharmacology/) Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given. Sources: [For Healthcare Professionals | FDA’s Examples of Drugs that Interact with CYP Enzymes and Transporter Systems](https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems) (U.S. Food and Drug Administration, 2026); [DailyMed - CLOPIDOGREL BISULFATE tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab32a331-2cea-453b-bba1-5451d38edd73) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - WARFARIN SODIUM tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8ad881e0-ca41-42ad-9d7d-eb85b3a30af0) (DailyMed (U.S. National Library of Medicine), 2026); [Grapefruit Juice and Some Drugs Don't Mix](https://www.fda.gov/consumers/consumer-updates/grapefruit-juice-and-some-drugs-dont-mix) (U.S. Food and Drug Administration, 2026). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/pharmacology/topics/drug-metabolism-and-cytochrome-p450/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/pharmacology/topics/drug-metabolism-and-cytochrome-p450/