Learning Objective
Differentiate between Phase I and Phase II biotransformation reactions, understand the role of CYP450 enzymes and genetic polymorphisms, and recognize clinical implications of slow/fast metabolism and conjugation pathways.
Phase I Reactions – Functionalization
Goal: Modify the drug molecule via oxidation, reduction, or hydrolysis.
Enzymes involved:
- Microsomal metabolism (Cytochrome P450 system)
- Located in the smooth endoplasmic reticulum of hepatocytes (also in the GI tract, lungs, kidney)
- Requires molecular oxygen and NADPH
- Oxidations: hydroxylation, dealkylation
- Multiple CYP families differing in substrate specificity and sensitivity to inhibitors/inducers
Major CYP450 Isozymes
| CYP450 | Substrate Example | Inducers | Inhibitors |
|---|---|---|---|
| 1A2 | Theophylline, Acetaminophen | Smoking, cruciferous vegetables | Quinolones, Fluvoxamine |
| 2C9 | Warfarin, NSAIDs | Rifampin, St. John’s Wort | Azole antifungals, Amiodarone, Sulfamethoxazole |
| 2C19 | PPIs, Clopidogrel | Rifampin, Carbamazepine, St. John’s Wort | Omeprazole, Cimetidine, Azole antifungals |
| 2D6 | Beta blockers, Antipsychotics, SSRIs/SNRIs | Rifampin | Amiodarone, Fluvoxamine, Haloperidol |
| 2E1 | Ethanol | Chronic ethanol consumption | Acute ethanol, Disulfiram, Metronidazole |
| 3A4 | Warfarin, Statins, Steroids | Rifampin, Carbamazepine, Phenytoin | Azole antifungals, Macrolides (except azithromycin), Grapefruit juice, Ritonavir |
Clinical Notes:
Nonmicrosomal Phase I metabolism
- Hydrolysis: Esterases, amidases (e.g., local anesthetics, succinylcholine)
- Monoamine oxidases (MAO): Dopamine, norepinephrine, serotonin, tyramine
- Alcohol dehydrogenases: Alcohol → aldehyde → acid; polymorphisms exist
Genetic polymorphisms:
- Slow acetylators (hydralazine, procainamide, INH) → longer half-life → increased risk of drug-induced SLE
Phase II Reactions – Conjugation
Goal: Add endogenous molecules to drugs for increased water solubility and excretion. May follow Phase I or occur directly.
Common Phase II Pathways
| Pathway | Features | Clinical Relevance |
|---|---|---|
| Glucuronidation | Inducible; enterohepatic cycling | Reduced in neonates → chloramphenicol toxicity; morphine → morphine-6-glucuronide |
| Acetylation | Genotypic variation (fast vs. slow) | Slow acetylators → SLE risk with hydralazine > procainamide > INH |
| Glutathione (GSH) conjugation | Detoxifies reactive metabolites | GSH depletion → acetaminophen hepatotoxicity |
