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


CONCLUSIONS
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.
Vormfelde
Stefan Viktor
SV
Department of Clinical Pharmacology, University Medical Cenger, Georg August University Göttingen, 37075 Göttingen, Germany.
Engelhardt
Sabine
S
Zirk
Alexandra
A
Meineke
Ingolf
I
Tuchen
Franziska
F
Kirchheiner
Julia
J
Brockmöller
Jürgen
J
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001711:Biotransformation; D065729:Cytochrome P-450 CYP2C9; D004231:Diuresis / Q000235:genetics; D004232:Diuretics / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000493:pharmacokinetics*; D000077786:Torsemide; D014527:Uric Acid / Q000378:metabolism
D004232:Diuretics; D013449:Sulfonamides; D014527:Uric Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000077786:Torsemide