Clinical pharmacology and therapeutics · 2004
CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide.
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Vormfelde Stefan Viktor, Engelhardt Sabine, Zirk Alexandra, Meineke Ingolf, Tuchen Franziska, Kirchheiner Julia, Brockmöller Jürgen
Аннотация
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.
RESULTS: 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 < .001). From 0 to 8 hours after torsemide administration, Na + , K + , and Cl - elimination was higher in carriers of CYP2C9*3 alleles than in carriers of the homozygous wild-type genotype, and 24-hour uric acid elimination values in urine were 451, 350, and 249 mg in carriers of 0, 1, and 2 CYP2C9*3 alleles, respectively (P = .003).
CONCLUSION: Torsemide pharmacokinetics differed significantly between subgroups with different CYP2C9 genotypes, and diuretic effects were slightly more exaggerated in carriers of CYP2C9*3 alleles. To answer the question of whether these findings have clinical implications, further studies in patients undergoing long-term torsemide treatment are required.
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.
RESULTS: 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 < .001). From 0 to 8 hours after torsemide administration, Na + , K + , and Cl - elimination was higher in carriers of CYP2C9*3 alleles than in carriers of the homozygous wild-type genotype, and 24-hour uric acid elimination values in urine were 451, 350, and 249 mg in carriers of 0, 1, and 2 CYP2C9*3 alleles, respectively (P = .003).
CONCLUSION: Torsemide pharmacokinetics differed significantly between subgroups with different CYP2C9 genotypes, and diuretic effects were slightly more exaggerated in carriers of CYP2C9*3 alleles. To answer the question of whether these findings have clinical implications, further studies in patients undergoing long-term torsemide treatment are required.