Real World Drug Metabolism Flashcards
What is interindividual variability in drug metabolism?
Interindividual variability refers to differences in drug metabolism among individuals due to genetic variations, environmental exposures (e.g., diet, smoking), lifestyle choices (e.g., alcohol consumption), and pathological factors (e.g., liver disease).
What are common causes of variable drug metabolism?
Causes include: (1) Drug-drug interactions: competition or inhibition of enzymes by co-administered drugs, altering drug levels. (2) Drug-diet interactions: foods affecting enzyme activity, such as grapefruit juice inhibiting CYP3A4. (3) Genetic variation: polymorphisms in genes encoding metabolizing enzymes, causing variability in enzymatic activity. (4) Underlying diseases: liver or kidney impairment reducing metabolism. (5) Environmental/lifestyle factors: smoking induces CYP1A2; alcohol affects multiple CYP enzymes.
What is a drug-drug interaction?
A drug-drug interaction occurs when one drug alters the metabolism of another, potentially leading to toxicity or reduced efficacy. For example, allopurinol inhibits xanthine oxidase, increasing the plasma levels of 6-mercaptopurine.
What is enzyme induction and an example?
Enzyme induction increases the synthesis of metabolizing enzymes, enhancing drug clearance. An example is rifampicin inducing CYP3A4, which also metabolizes its own substrate, reducing its efficacy (auto-induction).
What is a drug-diet interaction?
Drug-diet interactions occur when dietary components affect drug metabolism. Grapefruit juice inhibits CYP3A4, increasing systemic drug levels of substrates such as simvastatin, which can lead to toxicity.
What is the effect of CYP2D6 genetic variability on codeine metabolism?
CYP2D6 ultra-rapid metabolizers convert codeine to morphine at an accelerated rate, increasing the risk of morphine toxicity (e.g., respiratory depression). Poor metabolizers fail to convert sufficient codeine to morphine, resulting in reduced analgesic efficacy.
What is the ‘perfect storm’ of codeine toxicity?
The ‘perfect storm’ occurs when a CYP2D6 ultra-rapid metabolizer converts codeine to morphine excessively, transferring high morphine levels to a breastfeeding infant, leading to life-threatening respiratory depression.
What is irinotecan metabolism?
Irinotecan is a pro-drug activated by carboxylesterase 1 to SN-38, its active metabolite. SN-38 is inactivated by UGT1A1 through glucuronidation. Reduced UGT1A1 activity (e.g., in Gilbert’s syndrome) increases systemic SN-38 levels, causing severe diarrhea and neutropenia. Gut microflora can reconvert SN-38 glucuronide back to SN-38, exacerbating toxicity.
What is paracetamol toxicity and its antidote?
At high doses (>10 g), paracetamol is metabolized by CYP2E1 to NAPQI, a toxic electrophile. NAPQI depletes glutathione and binds to hepatic proteins, causing liver necrosis. The antidote, N-acetylcysteine, replenishes glutathione stores, neutralizing NAPQI if administered within 16 hours.
What is the role of NAT2 in isoniazid metabolism?
NAT2 acetylates isoniazid to acetyl-isoniazid. ‘Slow acetylators’ have reduced NAT2 activity, causing accumulation of hydrazine, a toxic metabolite that leads to hepatotoxicity. ‘Fast acetylators’ may clear the drug too quickly, reducing its efficacy.
How does clopidogrel metabolism affect its efficacy?
Clopidogrel is a pro-drug activated by CYP2C19 to R130964, its active metabolite, which inhibits platelet aggregation. Genetic polymorphisms reducing CYP2C19 activity (e.g., *2 and *3 alleles) impair activation, increasing the risk of thrombosis. Co-administration of CYP2C19 inhibitors (e.g., omeprazole) further reduces efficacy.
What are examples of toxic Phase I metabolites?
Toxic Phase I metabolites include: (1) NAPQI from paracetamol, causing hepatic necrosis. (2) Epoxides from carbamazepine, leading to hypersensitivity reactions. (3) Quinoneimines from phenacetin, linked to nephrotoxicity. (4) Free radicals from halothane, causing oxidative stress.
What are examples of drugs producing toxic Phase I metabolites?
(1) Paracetamol produces NAPQI via CYP2E1, leading to liver damage at high doses. (2) Isoniazid produces hydrazine, causing hepatotoxicity in slow acetylators. (3) Carbamazepine forms reactive epoxides, causing hypersensitivity and hepatotoxicity. (4) Halothane forms free radicals, causing oxidative damage and halothane hepatitis.
