Relationship between CYP2C9 genetic polymorphisms and effects of the loop diuretic torasemide

Abstract

According to in-vitro data, torasemide is a substrate of the genetically polymorphic enzyme CYP2C9 but the impact of CYP2C9 polymorphisms on torasemide pharmacodynamics has not yet been studied. 86 healthy volunteers received a single oral dose of 10 mg torasemide and the CYP2C9 Arg144Cys and Ile359Leu polymorphisms were analyzed by PCR. Under a salt-restricted diet urine volume and urinary elimination of sodium, potassium, chloride, and uric acid were measured in different factions over a period of 24 hours after drug administration. From 0 to 6 hours after torasemide administration, Na+, K+, and Cl− elimination was higher in carriers of one Leu359 variant than in homozygous wild-type genotype. Potassium excretion was 32, 37 and 41 mmol/6 h in carriers of CYP2C9 genotypes *1/*1, *1/*3, and *3/*3 (p=0.005 for trend). Uric acid elimination in the same interval was 93, 74, and 56 mg in carriers of *1/*1, *1/*3, and *3/*3, respectively. In the entire 24-hour-interval none of the CYP2C9-related differences were significant except for the fact that in carriers of the Leu359 variant the urinary elimination of uric acid was decreased. The arginine144cysteine polymorphism of CYP2C9 had no effects on urine volume, Na+, K+, Cl− or uric acid elimination. In conclusion, a minor repercussion of the genetic polymorphism in the torasemide metabolizing enzyme in effects and adverse effects was seen but the clinical impact of these differences is questionable. Clinical Pharmacology & Therapeutics (2004) 75, P66–P66; doi: 10.1016/j.clpt.2003.11.249