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.

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.

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.

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Example drugs

← All of 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 (U.S. Food and Drug Administration, 2026); DailyMed - CLOPIDOGREL BISULFATE tablet (DailyMed (U.S. National Library of Medicine), 2026); DailyMed - WARFARIN SODIUM tablet (DailyMed (U.S. National Library of Medicine), 2026); Grapefruit Juice and Some Drugs Don't Mix (U.S. Food and Drug Administration, 2026).

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