Pharmacokinetic studies of enantiomers of ibuprofen and its chiral metabolites in humans with different variants of genes coding CYP2C8 and CYP2C9 isoenzymes.
The pharmacokinetics of ibuprofen enantiomers and its chiral metabolites, namely (R,S)-29-hydroxyibuprofen and (RR,RS,SR,SS)-29-carboxyibuprofen, was studied in healthy volunteers carrying different alleles coding cytochrome P450 (CYP) 4502C isoenzymes. Following administration of 400 mg of racemic ibuprofen, enantiomers of the parent compound and their metabolites were isolated from plasma and urine samples using solid-phase extraction and were quantified by the validated capillary zone electrophoresis method. The levels of the analytes in biological fluids were used to calculate their pharmacokinetic parameters in subjects with different variants of CYP2C8 and CYP2C9 isoenzymes. The analysis of each subject's genotype was carried out using polymerase chain reaction-restriction fragment length polymorphism. Impaired metabolism of ibuprofen enantiomers was associated with the presence of CYP2C8*3, CYP2C9*2 and CYP2C9*3 alleles. The greatest effect of mutated alleles on pharmacokinetics was observed in a subject with a CYP2C8*1/*3, CYP2C9*1/*2 genotype. This subject appeared to have lower value of clearance, greater area under the curve (AUC) and longer time t(0.5) in comparison with the wild-type.
Karaźniewicz-Łada
M
M
Department of Physical Pharmacy and Pharmacokinetics, Poznań University of Medical Sciences, Poznań, Poland. mkaraz@ump.edu.pl
Luczak
M
M
Główka
F
F
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D019075:Electrophoresis, Capillary; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D052616:Solid Phase Extraction; D013237:Stereoisomerism
D007527:Isoenzymes; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D007052:Ibuprofen