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

Introduction: 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.

Methods: 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.

Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research.

This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2).