CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide

Abstract

According to in vitro data, torsemide (INN, torasemide) is a substrate of the genetically polymorphic enzyme cytochrome P450 (CYP) 2C9, but the impact of CYP2C9 polymorphisms on torsemide pharmacokinetics and pharmacodynamics has not been studied in humans. A total of 36 healthy volunteers (12, 9, 1, 9, 3, and 2 carriers of CYP2C9 genotypes*1/*1,*1/*2,*2/ *2,*1/*3,*2/*3, and*3/*3, respectively) received a single oral dose of 10 mg torsemide for pharmacokinetic and pharmacodynamic analysis. The effects of the CYP2C9 polymorphism on torsemide-induced urine volume and urinary elimination of sodium, potassium, chloride, and uric acid were measured during a salt-restricted diet. Median torsemide total oral clearance values were 3.4, 2.2, and 1.2 L/h in carriers of the CYP2C9 genotypes*1/*1,*1/*3, and*3/*3, respectively, but there was no significant difference related to CYP2C9*2. Values for metabolite formation clearance via metabolites M1 and M5 were 1.4, 1.7, 1.4, 1.0, 0.77, and 0.18 L/h in carriers of genotypes*1/*1, *1/*2,*2/*2,*1/*3,*2/*3, and*3/*3, respectively (P