Heritability of metformin renal clearance

Background Twin studies have been used to determine the genetic contribution to variation in hepatic drug metabolism. In contrast, little is known about the contribution of genetic factors to variation in renal drug elimination. In this study, we used monozygotic twin pairs to assess the heritability of the clearance of the anti-diabetic agent, metformin, a drug that is eliminated exclusively in the kidneys. Methods We administered 850 mg metformin to six monozygotic twin pairs and collected plasma and urine samples over 24 hours. Concentrations of metformin were determined by LC-MS. A modified calculation was used for assessing the heritability (H) of renal clearance: H= (Vbetween pairs− Vwithin pairs)/Vbetween pairs, where V is variance. Results In this interim analysis, we observed that 95% of the variation in renal clearance of metformin could be attributed to genetic factors (H=0.95), with an overall correlation coefficient of 0.97. Conclusions While the formal heritability calculation will require the enrollment of dizygotic twin pairs, this initial finding indicates that genetic factors contribute substantially to the renal clearance of metformin. The degree of heritability in renal clearance is similar to that observed in classical twin studies of drugs that are eliminated by hepatic metabolism. Clinical Pharmacology & Therapeutics (2005) 77, P61–P61; doi: 10.1016/j.clpt.2004.12.123