Medicinal Chemistry · Short notes

Drug Metabolism Chemistry: Short Notes & Cheat Sheet

Phase I and phase II reactions, the CYP450 enzymes, polymorphisms, enzyme induction and inhibition, and toxic metabolites.

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Short notes

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How the body clears a lipophilic drug

Phase I usually comes first, but a drug that already has a suitable group (e.g. morphine's –OH) can go straight to phase II.

Phase I (functionalisation)

Phase I adds or exposes a polar group (–OH, –NH₂, –COOH). The product may be active, inactive or toxic.
Oxidation by cytochrome P450 is the most important reaction: aromatic and aliphatic hydroxylation, N-, O- and S-dealkylation, N- and S-oxidation, and deamination.
Reduction: azo reduction (prontosil → sulfanilamide) and nitro reduction (chloramphenicol, nitrazepam), mostly by gut bacteria and liver enzymes.
Hydrolysis: esters are hydrolysed quickly by esterases (procaine, aspirin, succinylcholine by plasma cholinesterase); amides more slowly (lidocaine, procainamide).

Phase II (conjugation)

Glucuronidation (UGT enzymes, co-substrate UDPGA) is the most common. Newborns lack it, which explains grey baby syndrome with chloramphenicol and neonatal jaundice.
Sulfation (co-substrate PAPS) has low capacity and saturates easily. It is the main route for paracetamol in young children.
Acetylation (NAT2, acetyl-CoA) handles isoniazid, hydralazine, procainamide, dapsone and sulfonamides. Slow acetylators are more prone to toxicity.
Methylation (SAM; e.g. COMT) and acetylation make products less water-soluble, unlike the other conjugations.
Glutathione conjugation (GST) detoxifies reactive electrophiles such as NAPQI from paracetamol. Glycine conjugation turns benzoic acid into hippuric acid.

CYP enzymes and interactions

CYP3A4 metabolises about half of all drugs. CYP2D6 (codeine, tramadol, many antidepressants), CYP2C9 (warfarin, phenytoin) and CYP2C19 (clopidogrel, omeprazole) show genetic polymorphism.
Inducers speed metabolism (effect builds over 1–2 weeks): rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort, chronic alcohol and smoking (CYP1A2).
Inhibitors slow metabolism (effect within days): azole antifungals, macrolides (not azithromycin), cimetidine, ritonavir, isoniazid, grapefruit juice (gut CYP3A4).
Toxic metabolites: paracetamol → NAPQI, methanol → formic acid (blindness), cyclophosphamide → acrolein, halothane → trifluoroacetylated proteins (hepatitis).

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Phase II reactions

Reaction	Co-substrate · example
Glucuronidation	UDPGA · morphine, chloramphenicol, bilirubin
Sulfation	PAPS · paracetamol (children), steroids
Acetylation	Acetyl-CoA · isoniazid, hydralazine, dapsone
Methylation	SAM · catecholamines (COMT)
Glutathione	GSH · NAPQI (paracetamol)
Glycine	Glycine · benzoic acid → hippuric acid

Enzyme inducers vs inhibitors

Inducers	Inhibitors
Rifampicin	Ketoconazole, itraconazole
Carbamazepine	Erythromycin, clarithromycin
Phenytoin	Cimetidine
Phenobarbital	Ritonavir
St John's wort	Grapefruit juice
Smoking (1A2)	Ciprofloxacin (1A2), fluvoxamine

Memory aids

Inducers: 'CRAPS GP': Carbamazepine, Rifampicin, Alcohol (chronic), Phenytoin, St John's wort, Griseofulvin, Phenobarbital.
Acetylation and methylation are the odd ones out: Unlike other conjugations, they make metabolites less water-soluble.

Exam traps

Not every phase I metabolite is inactive: codeine becomes morphine, and diazepam gives active metabolites.
Acetylated sulfonamides are less soluble and can crystallise in urine.
Grapefruit juice mainly inhibits CYP3A4 in the gut wall, so it affects oral but not IV drugs.
Enzyme induction takes days to weeks to develop and to wear off; inhibition acts much faster.

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