Which genetic variant most significantly increases the risk of lactic acidosis in patients taking metformin, particularly when combined with iodinated contrast agents or renal impairment?
- A PMAT (SLC29A4) gain-of-function variants increasing renal tubular secretion
- B MATE1 (SLC47A1) gain-of-function variants increasing biliary metformin clearance
- C OCT1 (SLC22A1) loss-of-function variants reducing hepatic metformin uptake and increasing plasma levels ✓
- D CYP3A4 poor metabolizer variants increasing metformin plasma half-life
Explanation
Metformin is transported into hepatocytes primarily by OCT1 (organic cation transporter 1, SLC22A1). OCT1 loss-of-function variants (e.g., R61C, C88R, G401S) reduce hepatic uptake, meaning the drug cannot reach its site of action in the liver effectively. However, paradoxically, since OCT1 is also involved in intestinal absorption and distribution, certain variants alter the metformin pharmacokinetic profile significantly. More relevantly, OCT1 and OCT2 (renal) variants affect accumulation; reduced renal secretion (MATE1 loss-of-function, not gain-of-function) increases accumulation and lactic acidosis risk. Metformin is not metabolised by CYP enzymes; it is entirely excreted renally unchanged, making CYP variants irrelevant.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.