کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2561505 | 1126926 | 2008 | 8 صفحه PDF | دانلود رایگان |
Objectives(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.MethodsData 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.ResultsAllelic 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 AUC0−∞ 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 AUC0−∞ and t1/2 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%).ConclusionsThis 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.
Journal: Pharmacological Research - Volume 58, Issue 1, July 2008, Pages 77–84