A type 2 diabetic patient on metformin presents with lactic acidosis. Which pharmacokinetic property of metformin most predisposes to this complication when renal function is impaired?

• A Metformin is hepatically metabolised to a nephrotoxic metabolite that accumulates
• B Metformin induces CYP2C8, increasing production of lactate from glucose
• C Metformin inhibits renal gluconeogenesis, directly raising lactate levels
• D Metformin is entirely eliminated unchanged by the kidney; reduced GFR leads to drug accumulation ✓

Explanation

Metformin has negligible protein binding and is not metabolised by the liver; it is excreted unchanged by renal tubular secretion (OCT2 transporter). In renal impairment, metformin accumulates, inhibiting mitochondrial complex I in the liver and gut, impairing pyruvate oxidation and driving anaerobic glycolysis leading to lactic acidosis. This is why metformin is contraindicated when eGFR < 30 mL/min/1.73m².

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

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