DRUG METABOLISM

DEFINITION

the biochemical conversion (usually enzymic) of a drug to another chemical form (metabolite)

chemical form removal of drugs, terminate action of drug

SITES OF METABOLISM

MAJOR: LIVER

OTHER

GI tract
-digoxin is inactivated by intestinal bacteria
-NA and Adr metabolised by enzymes in intestinal wall

Lungs
-circulating prostaglandins are inactivated by enzymes in the lung
-bradykinin is metabolized by peptidases in the lung

Kidneys
-imipenem is metabolized by a dipeptidase in renal tubules

Blood
-Ach, ester LAs (except cocaine), are hydrolysed by plasma cholinesterase

FIRST PASS METABOLISM

can occur in

GI tract

portal circulation (e.g. aspirin)

liver (majority e.g propanolol, nifedipine, morphine, metoprolol)

50% bypasses = rectal route

Routes that avoid:

IV, SC, IM

buccal/ sublingual

inhalation

transdermal

oral drug -> gut wall -> portal blood -> liver -> systemic circulation

DRUG BIOTRANSFORMATION REACTIONS

Phase I reactions (Non-synthetic reactions)

Phase II (synthetic/ conjugation reactions)

convert lipophilic drugs -> more polar molecules by:
-adding polar functional groups (e.g. -OH, -NH2, -SH, -COOH) to a drug

reactions include:
-oxidation
-reduction
-hydrolysis

occur in sER (microsomal 'mixed function oxidase' system)
-also called monooxygenases, cP450 system

metabolites:
-excreted in urine/ undergo phase II reactions (if still too lipophilic)

reactive/ even toxic

add a conjugate to a drug/ its phase I metabolite with:
-highly polar endogenous substances (glucoronic acid, sulphate, glutathione, amino acid group, acetyl group, methyl group)

reaction include:
-glucoronidation (most common)
-conjugation with sulphate
-conjugation with gluthathione
-amino acid conjugation
-acetylation
-methylation

occur mainly in cytosol (except UGT which are microsomal)

metabolites:
-more polar
-can be excreted in kidney and bile
-almost always inactive except morphine 6-glucuronide

Phase II and then phase I (not common)

e.g; isoniazid- acetylated (phase II) and then hydrolysed (phase I) to isonicotinic acid and acetylhydrazine (hepatotoxic)

CLINICAL RELEVANCE OF DRUG METABOLISM

cumulative drug effects

if drug metabolites has longer half lives than parent drug, then drug effect may be prolonged

e.g; persistent CNS effect of diazepam can be partly attributed to one of its major metabolite desmethyldiazepam

specific metabolite-induced toxicity

P450 can activate some drugs to produce intermediates (highly reactive) and will react with cellular macromolecules (e.g proteins, DNA) to cause
-> specific toxic effects

e.g ; paracetamol induced hepatotoxicity

drug-drug interactions

enzyme induction

enzyme inhibition

activity of microsomal enzymes can be induced by many drugs with resultant acceleration of biotransformation rates

inhibition can occur with microsomal and non-microsomal enzyme, resulting in decreased biotransformation rates

genetic polymorphisms

acetylator status due to diff in hepatic N-acetyltransferase

SLOW ACETYLATORS
parent drug itself is toxic
e.g. isoniazid- induce polyneuritis

FAST ACETYLATORS (80% among eskimos, plynesians and asians, low among Mediterranean Jews)
acetylated metabolite is toxic
e.g; hepatitis induced by acetylhydrazine formed from isoniazid

Age

neonates

children

elderly (>65 yrs)

drug metabolizing capacity < adults

"grey baby syndrome" produced by cloramphenicol
-inability to metabolise antibiotic by glucuronidation due to deficiency of UDP-glucoronyl transferase

drug metabolise capacity > adult

faster clearance of iv theophyline than adults

decrease rate of metabolism

affect oxidative reactions
not affect conjugation