Xiaotao Q, Hall S D
Department of Medicine, Indiana University School of Medicine, Indianapolis.
J Pharmacol Exp Ther. 1993 Aug;266(2):845-51.
R-ibuprofen undergoes chiral inversion by the formation of a coenzyme A (CoA) thioester and subsequent epimerization and hydrolysis. Using isolated rat hepatocytes, the interaction of xenobiotics with the inversion and oxidation pathways of ibuprofen enantiomers was determined from the time course of R- and S-ibuprofen and ibuprofenyl-CoA during 4-hr incubations with R- or S-ibuprofen (25 microM). By fitting a first-order model, the rate constants of the formation of ibuprofenyl-CoA (K12), oxidation of R-ibuprofen (K10), hydrolysis of ibuprofenyl-CoA (K21) and oxidation of S-ibuprofen (K30) were 1.306, 0.284, 6.858 and 0.496 hr-1, respectively. The fractional inversion of R-ibuprofen was 0.75 and the area under the curve for ibuprofenyl-CoA was 203.8 microM min. Coincubation with 50 microM of the cytochrome P450 inhibitors metyrapone and proadifen resulted in significant reductions of K10 and K30; the fractional inversion of R-ibuprofen increased to 116% and 127% and the area under the curve of ibuprofenyl-CoA to 145% and 144% of controls, respectively. Valproic acid and pivalic acid at 50 microM significantly reduced the K12 and increased the K21; the fractional inversion was unchanged but the area under the curve of ibuprofenyl-CoA was significantly reduced to 57% and 28% of controls, respectively. Valproic acid also significantly reduced K10 and K30. p-nitrobenzoic acid at 50 microM significantly increased K21 and reduced the area under the curve of ibuprofenyl-CoA to 44% of control but did not influence the fractional inversion. Selective inhibitors of ibuprofen oxidation were found to enhance significantly hepatocellular exposure to the potentially reactive ibuprofenyl-CoA intermediate.
R-布洛芬通过形成辅酶A（CoA）硫酯以及随后的差向异构化和水解进行手性转化。使用分离的大鼠肝细胞，在与R-或S-布洛芬（25μM）进行4小时孵育期间，根据R-和S-布洛芬以及布洛芬-CoA的时间进程，确定了异生物素与布洛芬对映体的转化和氧化途径之间的相互作用。通过拟合一级模型，布洛芬-CoA形成的速率常数（K12）、R-布洛芬的氧化速率常数（K10）、布洛芬-CoA的水解速率常数（K21）和S-布洛芬的氧化速率常数（K30）分别为1.306、0.284、6.858和0.496小时-1。R-布洛芬的手性转化分数为0.75，布洛芬-CoA的曲线下面积为203.8μM·分钟。与50μM细胞色素P450抑制剂美替拉酮和丙磺舒共同孵育导致K10和K30显著降低；R-布洛芬的手性转化分数分别增加到对照的116%和127%，布洛芬-CoA的曲线下面积分别增加到对照的145%和144%。50μM的丙戊酸和新戊酸显著降低K12并增加K21；手性转化分数不变，但布洛芬-CoA的曲线下面积分别显著降低到对照的57%和28%。丙戊酸还显著降低K10和K30。50μM的对硝基苯甲酸显著增加K21并将布洛芬-CoA的曲线下面积降低到对照的44%，但不影响手性转化分数。发现布洛芬氧化的选择性抑制剂可显著增强肝细胞对潜在反应性的布洛芬-CoA中间体的暴露。
