A patient on metformin has a GFR that drops from 60 to 30 mL/min/1.73m² following contrast administration. Which pharmacokinetic reason necessitates metformin discontinuation?
- A Metformin is entirely renally excreted unchanged; reduced GFR causes drug accumulation increasing risk of lactic acidosis via mitochondrial complex I inhibition ✓
- B Contrast media forms a toxic conjugate with metformin causing direct nephrotoxicity
- C Reduced GFR increases metformin protein binding and free drug fraction
- D Metformin is metabolized by renal CYP450 enzymes that are impaired in renal failure
Explanation
Metformin has negligible protein binding and is not metabolized — it is excreted entirely unchanged by the kidneys via renal tubular secretion (OCT2 transporter) and glomerular filtration. When GFR falls below 30 mL/min/1.73m² (CKD stage 3b/4), metformin accumulates to toxic plasma concentrations. Metformin inhibits mitochondrial complex I (NADH:ubiquinone oxidoreductase), impairing pyruvate oxidation and causing pyruvate/lactate accumulation — the pathophysiological basis of metformin-associated lactic acidosis (MALA). Current guidelines (NICE, FDA) contraindicate metformin when eGFR <30, and advise caution 48 hours before and after contrast exposure.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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