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Abstract
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 t0.5 in comparison with the wild-type.
Acknowledgements
This study was supported by the Polish Ministry of Science and Higher Education (Grant Number 2P05F03529 (2006/2007)). The results presented in this paper were taken from the doctoral dissertation of M. Karaźniewicz-łada, submitted in partial fulfilment of the PhD requirements of the College of Pharmacy, Poznań, Poland, June 2007. The authors thank Professor P. Jagodziński, Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, for enabling the genetic studies to be performed.
Declaration of interest: The authors report no conflicts of interest.