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


CONCLUSIONS
Low ibuprofen clearance occurs in a substantial proportion of healthy subjects, is not enantiospecific, and is strongly linked to CYP2C8 and CYP2C9 polymorphisms.
García-Martín
Elena
E
Department of Biochemistry and Molecular Biology and Genetics, School of Biological Sciences, University of Extremadura, Badajoz, Spain.
Martínez
Carmen
C
Tabarés
Beatriz
B
Frías
Jesús
J
Agúndez
José A G
JA
D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001682:Biological Availability; D016009:Chi-Square Distribution; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D011110:Polymorphism, Genetic; D011336:Probability; D011446:Prospective Studies; D012016:Reference Values; D012680:Sensitivity and Specificity
D000596:Amino Acids; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D007052:Ibuprofen