Chapter 2 · Module 3 of 5 · Pharmacokinetics

Metabolism and Biotransformation

CYP450 isoforms, Phase I and II reactions, low- vs. high-extraction hepatic clearance, enzyme induction and inhibition, and pharmacogenomic prodrug interactions

CYP3A4 metabolizes approximately 50% of all drugs and is the most clinically important CYP isoform; it is inhibited by azole antifungals, macrolides, and ritonavir (raising substrate levels) and induced by rifampin, carbamazepine, and St. John's wort (lowering substrate levels); grapefruit irreversibly inhibits intestinal CYP3A4 for 24–72 hours
Phase II conjugation (glucuronidation, acetylation, sulfation) converts drug or Phase I metabolites into water-soluble conjugates for excretion; morphine-6-glucuronide is an active and toxic metabolite that accumulates in renal failure; neonatal glucuronidation deficiency causes gray baby syndrome with chloramphenicol; NAT2 slow acetylators accumulate isoniazid and are at greater risk of neuropathy, hepatotoxicity, and drug-induced lupus
Low-extraction drugs (warfarin, phenytoin, theophylline) are sensitive to enzyme inhibitor interactions — inhibition causes large rises in plasma levels; high-extraction drugs (lidocaine, morphine, propranolol) are sensitive to hepatic blood flow — cirrhosis or reduced cardiac output dramatically reduces clearance
Enzyme induction (rifampin most potent) takes 1–3 weeks to develop and causes treatment failure of substrates; enzyme inhibition takes hours to days and causes toxicity of substrates; mechanism-based irreversible inhibition (grapefruit, clarithromycin, erythromycin) persists until new enzyme is synthesized
For prodrugs, the usual pharmacogenomic rules reverse: CYP2D6 poor metabolizers get no analgesia from codeine (no morphine generated) but ultrarapid metabolizers risk fatal respiratory depression; CYP2C19 poor metabolizers get inadequate platelet inhibition from clopidogrel (stent thrombosis risk); adding CYP2D6 inhibitors like fluoxetine to tamoxifen reduces active endoxifen and may increase breast cancer recurrence risk

Section 1 — Key CYP Isoforms — Substrates, Inhibitors, and Inducers

Section 1 — Phase I

CYP450 Isoform Reference Table

Isoform	Key Substrates	Key Inhibitors	Key Inducers
CYP3A4	Statins (simvastatin, lovastatin, atorvastatin), cyclosporine, tacrolimus, benzodiazepines, calcium channel blockers, many others (~50% of drugs)	Azole antifungals, macrolides, ritonavir, grapefruit (intestinal, irreversible 24–72 h)	Rifampin, carbamazepine, phenytoin, phenobarbital, St. John's wort
CYP2C9	Warfarin (S-enantiomer), NSAIDs, phenytoin, sulfonylureas	Fluconazole, amiodarone, metronidazole	Rifampin, carbamazepine
CYP2C19	PPIs (omeprazole, pantoprazole), clopidogrel (activation), diazepam, SSRIs	Omeprazole, fluconazole, fluvoxamine	Rifampin
CYP2D6	Codeine (activation to morphine), tramadol, TCAs, SSRIs, metoprolol, tamoxifen (activation to endoxifen)	Fluoxetine, paroxetine, bupropion, quinidine	None clinically significant
CYP1A2	Theophylline, clozapine, caffeine, olanzapine	Fluvoxamine, ciprofloxacin	Cigarette smoking, omeprazole

Acetaminophen toxicity: CYP2E1 converts acetaminophen → NAPQI, a reactive electrophile. Normally conjugated by glutathione. In overdose or glutathione depletion (fasting, chronic alcohol use): NAPQI accumulates → hepatocyte necrosis. Antidote: NAC replenishes glutathione. Most effective within 8 hours of ingestion.

Section 2 — Phase II Reactions — Conjugation

Section 2

Glucuronidation, Acetylation, and Clinical Consequences

Glucuronidation (UGT Enzymes)

Major Conjugation Pathway

Attaches glucuronic acid → water-soluble conjugate, renally or biliarily excreted
Morphine-6-glucuronide: active opioid metabolite — accumulates in renal failure, causes prolonged sedation and respiratory depression
UGT enzymes immature at birth — slow neonatal glucuronidation
Gray baby syndrome: chloramphenicol accumulates in neonates → cardiovascular collapse

Acetylation (NAT2 Enzyme)

Slow vs. Rapid Acetylator Phenotype

Substrates: isoniazid, hydralazine, procainamide, dapsone
Slow acetylators (40–70% in European and Middle Eastern populations): drug accumulates more
Isoniazid: slow acetylators → more peripheral neuropathy and hepatotoxicity risk
Hydralazine and procainamide: slow acetylators → more drug-induced lupus syndrome

Section 3 — Hepatic Clearance — Low-Extraction vs. High-Extraction

Section 3

Capacity-Limited vs. Flow-Limited Hepatic Drug Elimination

Feature	Low-Extraction (Capacity-Limited)	High-Extraction (Flow-Limited)	Clinical Implication
Extraction ratio	< ~0.3	> ~0.7	Determines first-pass magnitude
Rate-limiting factor	Enzyme activity and drug concentration	Hepatic blood flow	Dictates which interventions change clearance
Effect of enzyme inhibitor	Large rise in plasma level — toxicity risk	Smaller effect than expected	Inhibitor interactions most dangerous for low-extraction drugs
Reduced blood flow (cirrhosis, hypotension)	Minimal effect on clearance	Major rise in plasma level — toxicity risk	Reduce high-extraction drug doses in cirrhosis or low-output states
Examples	Warfarin, phenytoin, theophylline, diazepam	Lidocaine, morphine, propranolol, verapamil	Know which category before adjusting dosing

Section 4 — Enzyme Induction and Inhibition

Section 4

Induction (Treatment Failure) vs. Inhibition (Toxicity)

Enzyme Induction

Faster Metabolism → Lower Levels

Onset: gradual (1–3 weeks); offset: gradual after stopping
Effect: lower plasma concentrations → treatment failure
Rifampin: most potent inducer (CYP3A4, 2C9) — reduces substrate levels 80–90%
Others: carbamazepine, phenytoin, phenobarbital, St. John's wort
Key interactions: rifampin + warfarin (loss of anticoagulation), rifampin + oral contraceptives (failure), St. John's wort + cyclosporine (rejection)

Enzyme Inhibition

Slower Metabolism → Higher Levels

Onset: rapid (hours to days); offset: rapid (except mechanism-based)
Effect: higher plasma concentrations → toxicity
CYP3A4: azole antifungals, macrolides, ritonavir — statin myopathy, cyclosporine toxicity
CYP2C9: fluconazole, amiodarone → potentiate warfarin → bleeding
CYP2D6: fluoxetine, paroxetine → raise TCA levels, abolish codeine analgesia
Mechanism-based (irreversible): grapefruit (24–72 h), erythromycin, clarithromycin

Sections 5 & 6 — Pharmacogenomics and Prodrug Activation

Sections 5 & 6

Metabolizer Phenotype Consequences for Prodrugs

Drug	CYP	Poor Metabolizer Effect	Ultrarapid Metabolizer Effect	Key Clinical Action
Codeine	2D6	No analgesia (no morphine generated)	Morphine toxicity, respiratory depression — FDA black box warning	Avoid in breastfeeding mothers; avoid CYP2D6 inhibitors with codeine
Clopidogrel	2C19	Inadequate platelet inhibition → stent thrombosis — FDA black box warning	Possibly greater effect (uncertain clinical significance)	Consider prasugrel or ticagrelor in poor 2C19 metabolizers; prefer pantoprazole over omeprazole with clopidogrel
Tamoxifen	2D6	Low endoxifen → higher breast cancer recurrence risk	Higher endoxifen (uncertain benefit)	Avoid fluoxetine and paroxetine with tamoxifen; use sertraline or venlafaxine if antidepressant is needed
Warfarin	2C9	Reduced clearance → elevated INR, bleeding risk at standard doses	Possible dose resistance	Use lower doses in 2C9 poor metabolizers; incorporate genotype in dosing algorithm

The prodrug reversal rule: For prodrugs (codeine, clopidogrel, tamoxifen), the usual pharmacogenomic consequences are reversed. A CYP2D6 inhibitor added to codeine does not reduce toxicity risk — it eliminates efficacy by preventing morphine formation. Adding fluoxetine or paroxetine to a tamoxifen regimen does not reduce tamoxifen's side effects — it may reduce cancer protection by lowering active endoxifen levels.

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Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition	McGraw-Hill, 2023
Brunton LL, Hilal-Dandan R, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition	McGraw-Hill, 2018
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