Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms*1

Abstract

OBJECTIVE: Our objective was to identify genetic factors related to interindividual variability in the pharmacokinetics of ibuprofen and its enantiomers. METHODS: The time course for ibuprofen plasma concentration was measured by HPLC in 130 healthy individuals who received a single oral dose of 400 mg racemic ibuprofen. Genomic deoxyribonucleic acid was analyzed for common mutations at CYP2C8 and CYP2C9 genes that cause amino acid substitutions. RESULTS: Ibuprofen clearance values were 4.04 L/h (95% confidence interval [CI], 3.61-4.47 L/h), 2.79 L/h (95% CI, 2.07-3.52 L/h), and 0.40 L/h (95% CI, 0.37-0.43 L/h) for carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, and 4.43 L/h (95% CI, 3.94-4.92 L/h), 3.26 L/h (95% CI, 2.53-3.99 L/h), 2.91 L/h (95% CI, 1.52-4.30 L/h), 2.05 L/h (95% CI, 0-6.37 L/h), 1.83 L/h (95% CI, 1.24-2.41 L/h), and 1.13 L/h (95% CI, 0.58-1.66 L/h) for carriers of the CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. The P values for comparison across nonmutated, heterozygous, and homozygous genotypes were as follows: P <.001 for CYP2C8*3, P <.005 for CYP2C9*2, and P <.001 for CYP2C9*3. The main genetic factor for reduced clearance of R-(-)-ibuprofen is the CYP2C8*3 allele, whereas the clearance for S-(+)-ibuprofen is influenced by CYP2C8*3 and CYP2C9*3 alleles to a similar extent. The CYP2C9*2 allele was associated with low clearance only when it was present in combination with the CYP2C8*3 allele. As compared with individuals with no mutations, individuals with the common genotype CYP2C8*1/*3 plus CYP2C9*1/*2 (19% of the population) displayed decreased ibuprofen clearance (mean, 65% [95% CI, 42%-89%]; P <.001). Individuals homozygous or double-heterozygous for CYP2C8*3 and CYP2C9*3 variant alleles (8% of the population) had extremely low ibuprofen clearance rates, with values ranging from 7% to 27% of the mean clearance rates among noncarriers of mutations (P <.001). No enantiospecific reduction of ibuprofen clearance was observed. CONCLUSION: Low ibuprofen clearance occurs in a substantial proportion of healthy subjects, is not enantiospecific, and is strongly linked to CYP2C8 and CYP2C9 polymorphisms.