Effects of ibuprofen on the disposition kinetics of phenytoin in pregnant rats

Abstract

The effects of ibuprofen on maternal phenytoin pharmacokinetics and fetal phenytoin acquisition were investigated in 19-day gestation Sprague-Dawley rats. A 5 mg kg-1 bolus injection of 14C-phenytoin was given with and without (control) pretreatment with 12.5 mg kg-1 of ibuprofen. Maternal plasma and fetal whole body samples were obtained at various times after the phenytoin bolus and evaluated simultaneously using a three-compartment maternal-fetal model. Ibuprofen pretreatment increased the maternal plasma clearance of phenytoin about three-fold and the overall apparent volume of distribution almost four-fold. No changes in the volume of the maternal central compartment or terminal first-order disposition rate constant were observed. Additionally, the maternal-to-fetal clearance of phenytoin was not altered in the ibuprofen-treated rats. No differences in the apparent fetal volume of distribution or areas under the fetal phenytoin concentration-time curves were observed between the control and ibuprofen-treated rats. The results of this study were consistent with ibuprofen-induced alterations in organ and tissue blood perfusion and demonstrated that, while the maternal disposition kinetics of phenytoin were altered by sodium ibuprofen coadministration, the maternal changes did not affect the extent of fetal exposure to phenytoin.