Goto M, Ohnishi C, Yamashina H, Johno I, Kitazawa S
J Pharmacobiodyn. 1987 Jan;10(1):8-14. doi: 10.1248/bpb1978.10.8.
The effects of valproic acid (VPA) on pharmacokinetics of cyclophosphamide (CPM) alkylating metabolites were investigated in male BALB/c mice. The pharmacokinetics of CPM alkylating metabolites was found to be dose-dependent representing the decrease of formation and elimination rates of the metabolites. A nonlinear increase of area under blood concentration of CPM alkylating metabolites-time curve (AUC) occurred with increasing CPM dose of 100, 200, and 300 mg/kg body weight. The effects of VPA (100 mg/kg dose) coadministered with CPM were similar to those of the increase of the CPM dose in preventing the activation of CPM and the elimination of its alkylating metabolites. The delayed disposition of CPM alkylating metabolites resulted in a 1.5-fold increase (p less than 0.02) of AUC which was considered the most important pharmacokinetic parameter in the CPM therapy. VPA which was injected i.p. at a dose of 100, 200, or 300 mg/kg increased the pentobarbital induced-sleep time by 81, 138, or 192%, respectively. In order to assess the effect of VPA on drug metabolizing enzyme(s) activity in humans, the ratio of daily urinary 6-hydroxycortisol to 17-hydroxycorticosteroids, which can reflect cytochrome P-450 activity, was determined in 5 healthy volunteers. The ratio was rapidly and significantly decreased (p less than 0.05) and this reduction continued during VPA administration. These findings and those reported in the literature concerning CPM metabolism suggest that the delay of CPM alkylating metabolites elimination resulted in part from microsomal enzyme(s) inhibition by VPA.
在雄性BALB/c小鼠中研究了丙戊酸（VPA）对环磷酰胺（CPM）烷基化代谢产物药代动力学的影响。发现CPM烷基化代谢产物的药代动力学呈剂量依赖性，表现为代谢产物形成和消除速率的降低。随着CPM剂量增加至100、200和300mg/kg体重，CPM烷基化代谢产物血药浓度-时间曲线下面积（AUC）呈非线性增加。与CPM联合使用的VPA（100mg/kg剂量）的作用与增加CPM剂量在预防CPM活化及其烷基化代谢产物消除方面的作用相似。CPM烷基化代谢产物的处置延迟导致AUC增加了1.5倍（p<0.02），这被认为是CPM治疗中最重要的药代动力学参数。腹腔注射剂量为100、200或300mg/kg的VPA分别使戊巴比妥诱导的睡眠时间增加了81%、138%或192%。为了评估VPA对人体药物代谢酶活性的影响，在5名健康志愿者中测定了可反映细胞色素P-450活性的每日尿6-羟基皮质醇与17-羟基皮质类固醇的比值。该比值迅速且显著降低（p<0.05），且在VPA给药期间持续下降。这些发现以及文献中关于CPM代谢的报道表明，CPM烷基化代谢产物消除延迟部分是由于VPA对微粒体酶的抑制作用。
