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Drug Metabolism and Elimination (Pro-Drugs (L-Dopa → dopamine, Enalapril →…
Drug Metabolism and Elimination
First Pass Metabolism
Metabolism and inactivation of a drug before it reaches the systemic circulation.
i.e. pre-systemic elimination
Occurs in gut wall and liver
E.g. propranolol, verapamil, morphine, nitrates
Cytochrome P450 System
Most important system of phase 1 metabolism
11 subtypes
CyP3A4
Most important subtype
≥ 30% of drugs: CCBs, β-B, statins, benzos
CyP2D6
Second most important
≥20% of drugs: antidepressants, some β-B,
opiates
Pharmacogenomics
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Genetically determined variation in drug response
Acetylation
Fast vs. slow acetylators (↑↑ fast in Japan vs. Europe)
Affects: isoniazid, hydralazine and dapsone
Oxidation
There are genetic polymorphisms for all known CyP450 enzymes except for CyP3A4
G6PD Deficiency
Oxidative stress → haemolysis
Quinolones, primaquine, nitrofurantoin, dapsone
Acute Intermittent Porphyria
AD, ↑ in White South Africans
Large no. of drugs can → attacks: e.g. EtOH, NSAIDs…
Pathways of Drug Metabolism and Elimination
Excrete unchanged by the kidney (e.g. frusemide)
Elimination: mainly renal (depends on GFR)
Phase 1 metabolism then renal excretion
Creation of reactive, polar functional groups
Oxidation: usually by CyP450 system
Reduction and hydrolysis
Phase 2 metabolism then renal excretion
Production of polar compounds for renal elimination
Either the drug or its phase 1 metabolite
Conjugation reactions
Glucuronidation, sulfonation, acetylation, methyl
Pro-Drugs
L-Dopa → dopamine
Enalapril → enalaprilat
Ezetimibe → ez-glucuronide
Methyldopa → α-methylnorepinephrine
Azathioprine → 6-mercaptopurine (by XO)
Carbimazole → methimazole
Cyclophosphamide