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

摘要: Introduction According to in vitro data, torsemide (INN, torasemide) is a substrate of the genetically polymorphic enzyme cytochrome P450 (CYP) 2C9, but impact CYP2C9 polymorphisms on pharmacokinetics and pharmacodynamics has not been studied humans. Methods A total 36 healthy volunteers (12, 9, 1, 3, 2 carriers genotypes *1/*1, *1/*2, *2/*2, *1/*3, *2/*3, *3/*3, respectively) received single oral dose 10 mg for pharmacokinetic pharmacodynamic analysis. The effects polymorphism torsemide-induced urine volume urinary elimination sodium, potassium, chloride, uric acid were measured during salt-restricted diet. Results Median clearance values 3.4, 2.2, 1.2 L/h respectively, there was no significant difference related CYP2C9*2. Values metabolite formation via metabolites M1 M5 1.4, 1.7, 1.0, 0.77, 0.18 respectively (P < .001). From 0 8 hours after administration, Na+, K+, Cl− higher CYP2C9*3 alleles than homozygous wild-type genotype, 24-hour 451, 350, 249 0, alleles, = .003). Conclusion Torsemide differed significantly between subgroups with different genotypes, diuretic slightly more exaggerated alleles. To answer question whether these findings have clinical implications, further studies patients undergoing long-term treatment are required. Clinical Pharmacology & Therapeutics (2004) 76, 557–566; doi: 10.1016/j.clpt.2004.08.024