Expansion
Phase I modifies the molecule; phase II conjugates it
Mnemonic
SICKFACES.COM for the cytochrome P450 inhibitors, which raise drug levels:
- S - Sodium valproate
- I - Isoniazid
- C - Cimetidine
- K - Ketoconazole and the azoles
- F - Fluconazole
- A - Alcohol, acute binge
- C - Chloramphenicol
- E - Erythromycin and the macrolides
- S - Sulphonamides
- C - Ciprofloxacin
- O - Omeprazole
- M - Metronidazole
And CRAP GPS for the inducers, which lower drug levels:
- C - Carbamazepine
- R - Rifampicin
- A - Alcohol, chronic
- P - Phenytoin
- G - Griseofulvin
- P - Phenobarbitone
- S - Sulphonylureas, and St John’s wort
“Inhibitors act in days, inducers take weeks”, because inhibition is competitive and immediate whereas induction requires new enzyme synthesis. The drugs where this matters most are warfarin, the combined oral contraceptive, ciclosporin, phenytoin and the direct oral anticoagulants.
Expansion
Phase I: modification (oxidation, reduction, hydrolysis)
- Mainly by cytochrome P450 enzymes in hepatic endoplasmic reticulum
- Adds or exposes a functional group
- May produce an active metabolite (codeine to morphine, enalapril to enalaprilat) or a toxic one (paracetamol to NAPQI)
Phase II: conjugation
- Glucuronidation, sulphation, acetylation, methylation, glutathione conjugation
- Makes the molecule water soluble for renal or biliary excretion
- Almost always inactivating, with morphine-6-glucuronide a notable exception
Not all drugs undergo both, and some undergo phase II alone.
Genetic variation matters clinically:
- CYP2D6 polymorphism: poor metabolisers get no analgesia from codeine (which needs conversion to morphine), while ultrarapid metabolisers risk toxicity, which is why codeine is avoided in breastfeeding and in children
- Acetylator status: slow acetylators are prone to isoniazid neuropathy and to drug-induced lupus with hydralazine and procainamide
- TPMT deficiency causes severe azathioprine toxicity, so it is tested before starting