Which pharmacogenomic variation most significantly alters the clinical response to metoprolol, and what is the functional consequence of the 'poor metaboliser' phenotype?

• A CYP3A4 poor metaboliser — increased first-pass metabolism leading to reduced bioavailability
• B UGT1A1 poor metaboliser — accumulation of metoprolol glucuronide causing hepatotoxicity
• C CYP2C19 ultra-rapid metaboliser — reduced metoprolol levels and loss of antihypertensive effect
• D CYP2D6 poor metaboliser — significantly higher plasma metoprolol levels, increased beta-blockade and bradycardia risk ✓

Explanation

Metoprolol is primarily metabolised by CYP2D6. Poor metabolisers (carrying two non-functional CYP2D6 alleles, e.g., *4/*4) exhibit up to 10-fold higher plasma drug concentrations, resulting in excessive beta-blockade with profound bradycardia, hypotension, and bronchospasm at standard doses. This is a classic example of pharmacogenomics influencing drug safety; dose reduction is recommended in CYP2D6 poor metabolisers. CYP3A4 has a minor role; CYP2C19 is not relevant; UGT1A1 variants affect irinotecan/bilirubin metabolism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.