STEPTRACKERPHARMACOLOGY + GENETICS | DRUG METABOLISM | HIGH-YIELD REVIEW

Drug Metabolism, CYP450 & Pharmacogenomics

The liver makes drugs more water-soluble in two phases; the CYP enzymes of phase I explain most drug interactions, and inherited enzyme variants explain many unexpected toxicities.

FOCUS ON
Phase I (CYP450): oxidation, reduction, hydrolysis → slightly polar, may stay active or become toxic; declines in the elderly. Phase II (conjugation): glucuronidation, acetylation, sulfation, glutathione → very polar, inactive, excreted; relatively preserved with age (except acetylation varies). CYP inducers (↓ partner levels): rifampin, carbamazepine, phenytoin, phenobarbital, griseofulvin, St John's wort, chronic alcohol, smoking (1A2). CYP inhibitors (↑ partner levels): azoles, macrolides (not azithromycin), ritonavir/cobicistat, grapefruit juice, amiodarone, cimetidine, isoniazid, valproate, fluoxetine/paroxetine (2D6), acute alcohol. Narrow-index victims: warfarin, OCPs, cyclosporine/tacrolimus, theophylline, statins. Pharmacogenomics: slow acetylators (isoniazid neuropathy, drug-induced lupus), G6PD deficiency, TPMT, CYP2C19 (clopidogrel), CYP2D6 (codeine), HLA-B*57:01, B*15:02, B*58:01, pseudocholinesterase.
TOPIC
DETAIL
EXAMPLES
CLINICAL RESULT
Phase I reactions
CYP450 oxidation, reduction, hydrolysis (smooth ER)
Most lipophilic drugs
Can create toxic metabolites (acetaminophen → NAPQI)
Phase II reactions
Conjugation: glucuronide, acetyl, sulfate, glutathione, methyl
Morphine glucuronide, isoniazid acetylation
Neonates lack glucuronidation → gray baby syndrome (chloramphenicol)
Prodrugs
Need metabolism to become active
Clopidogrel, codeine, cyclophosphamide, enalapril, levodopa, azathioprine, valacyclovir, tamoxifen
Genetic or drug-induced loss of activation → treatment failure
CYP inducers
↑ enzyme synthesis (days to weeks)
Rifampin, carbamazepine, phenytoin, phenobarbital, griseofulvin, St John's wort, chronic ethanol, smoking
↓ warfarin effect, OCP failure, transplant rejection, ART failure
CYP inhibitors
Block enzyme (immediate)
Azoles, clarithromycin/erythromycin, ritonavir, grapefruit, amiodarone, cimetidine, isoniazid, valproate, fluoxetine, acute alcohol
Bleeding on warfarin, statin myopathy, calcineurin toxicity, QT
CYP3A4
Metabolizes ~half of drugs
Statins (simva, atorva), CCBs, tacrolimus, cyclosporine, protease inhibitors, midazolam
Pravastatin, rosuvastatin less affected
CYP2D6
Polymorphic
Codeine → morphine, tramadol, tamoxifen activation, many antidepressants, β-blockers
Ultrarapid: codeine overdose (fatal in breastfed infants) · poor: no analgesia
CYP2C19 · CYP2C9
Clopidogrel activation · warfarin (S-isomer), phenytoin
Poor 2C19 metabolizers
Stent thrombosis on clopidogrel · VKORC1/2C9 genotypes guide warfarin dose
N-acetyltransferase (NAT2)
Fast vs slow acetylators
Isoniazid, hydralazine, procainamide, dapsone, sulfasalazine
Slow: neuropathy, drug-induced lupus
G6PD deficiency
↓ NADPH → oxidant-induced hemolysis
Primaquine, dapsone, sulfonamides, nitrofurantoin, rasburicase, methylene blue, fava beans
Heinz bodies, bite cells
TPMT · DPD · UGT1A1
Thiopurine · fluorouracil · irinotecan metabolism
Azathioprine, 6-MP · 5-FU · irinotecan
Severe marrow toxicity (Gilbert variant → irinotecan)
Pseudocholinesterase deficiency
Can't break down succinylcholine
Inherited
Prolonged apnea after anesthesia
HLA-linked reactions
Drug-specific T-cell activation
B*57:01 (abacavir), B*15:02 (carbamazepine), B*58:01 (allopurinol)
Test before prescribing

Mechanism — inducer vs inhibitor

Inducer (rifampin)
→
More CYP enzymeOver 1–2 weeks
→
Partner drug cleared faster → fails
Inhibitor (ketoconazole)
→
Enzyme blockedWithin days
→
Partner drug accumulates → toxicity

Classic interaction pairs

PAIR
MECHANISM
RESULT
Rifampin + OCP
Induction
Pregnancy
Clarithromycin + simvastatin
3A4 inhibition
Rhabdomyolysis
Fluconazole + warfarin
2C9 inhibition
Bleeding
Omeprazole + clopidogrel
2C19 inhibition
Less antiplatelet effect
Carbamazepine + itself
Autoinduction
Levels fall over weeks

How it's tested

COMMON CONFUSIONAcute alcohol inhibits CYP (↑ warfarin effect); chronic alcohol induces it (↓ effect, ↑ acetaminophen toxicity).
THE TRAPStopping an inducer is also dangerous — the partner drug's level rises as enzyme levels fall back (e.g., warfarin after rifampin ends).
YOUR APPROACHName the narrow-index drug → is the new drug an inducer or inhibitor → which way the level moves → expected toxicity or failure.

If you see… think…

OCP failure on TB therapy → rifampin induction
INR rises after starting fluconazole → CYP2C9 inhibition
Muscle pain on simvastatin after clarithromycin → CYP3A4 inhibition
Infant opioid toxicity, mother on codeine → CYP2D6 ultrarapid metabolizer
Stent thrombosis on clopidogrel → CYP2C19 poor metabolizer
Neuropathy and lupus-like illness on isoniazid → slow acetylator
Hemolysis after primaquine → G6PD deficiency
Prolonged paralysis after succinylcholine → pseudocholinesterase deficiency
Drugs needing activation → prodrugs (clopidogrel, codeine, cyclophosphamide)
Phase II reaction lacking in newborns → glucuronidation