Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers.
OBJECTIVE
(i) To define the incidence of alleles CYP2C8*1 to *5 in a Spanish population; (ii) to test the impact of such alleles, and those of CYP2C9, on the metabolism of racemic ibuprofen, R-ibuprofen and S-ibuprofen; and (iii) to discern whether those metabolic alterations have safety implications.


METHODS
Data from three phase I clinical trials with 69 healthy volunteers taken ibuprofen were analyzed. Genotyping were performed by PCR. Pharmacokinetic parameters were determined in studies 1 and 2 by non-compartmental analysis. Levels of COX-1, COX-2, eNOS and iNOS were determined by Western Blots in gastric biopsies of study 3.


RESULTS
Allelic frequencies were 0.80, 0.02, 0.11, 0.07 and 0 for CYP2C8*1, *2, *3, *4 and *5. CYP2C9*3 allele had a decreased racemic ibuprofen metabolism, leading to a 30% augmentation of AUC(0-infinity) and a 30% reduction of clearance compared to CYP2C9*1 (p < 0.05). CYP2C8*3 had a 20% augmentation of clearance compared to CYP2C8*1 (p < 0.05) of R-ibuprofen. CYP2C9*3 had a 45% reduction of clearance, as well as a 87% and 47% augmentation of AUC(0-infinity) and t(1/2) with respect to CYP2C9*1 of S-ibuprofen and a 30% reduction of clearance of R-ibuprofen. A decreased iNOS expression was found in CYP2C8*3 compared to wild type (p < 0.05). Adverse events in CYP2C8*3 (20%) and *4 (20%) were fewer than in CYP2C8*1 (77%).


CONCLUSIONS
This study suggest an impaired metabolism of racemic, S-ibuprofen and R-ibuprofen in CYP2C9*3; an increased R-ibuprofen metabolism in CYP2C8*3; and fewer adverse events in CYP2C8*3 volunteers; that correlates with a decreased expression of iNOS.
López-Rodríguez
Rosario
R
Clinical Pharmacology Service, Instituto Teófilo Hernando, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Novalbos
Jesús
J
Gallego-Sandín
Sonia
S
Román-Martínez
Manuel
M
Torrado
Juan
J
Gisbert
Javier P
JP
Abad-Santos
Francisco
F
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001682:Biological Availability; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D044465:White People; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D007052:Ibuprofen