Genetic variation at the CYP2C locus and its association with torsemide biotransformation.
In 97 unselected volunteers and two additional homozygous carriers of CYP2C9(*)3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9(*)3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl- and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9(*)3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9(*)3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r(2)=82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9(*)3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.
Vormfelde
S V
SV
Department of Clinical Pharmacology, University Medical Centre, Georg-August-University, Göttingen, Germany. svormfe@gwdg.de
Schirmer
M
M
Toliat
M R
MR
Meineke
I
I
Kirchheiner
J
J
Nürnberg
P
P
Brockmöller
J
J
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001711:Biotransformation; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013449:Sulfonamides / Q000493:pharmacokinetics*; D000077786:Torsemide
D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000077786:Torsemide