Doxorubicin alters the disposition of phenytoin by reducing its metabolic elimination and binding affinity to serum albumin in rats
Doxorubicin alters the disposition of phenytoin by reducing its metabolic elimination and binding affinity to serum albumin in rats
复制标题
阿霉素通过降低大鼠体内苯妥英的代谢消除和与血清白蛋白的结合亲和力来改变苯妥英的处置
DOI：
10.1093/jpp/rgab169
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发表时间：
2021
影响因子：
3.3
通讯作者：
Konishi Hiroki
中科院分区：
文献类型：
--
作者：
Fukuno Shuhei;Nagai Katsuhito;Yamaoka Shizuka;Yamada Fuka;Mizumoto Haruna;Ito Takuya;Konishi Hiroki
ObjectivesWe研究了阿霉素（DOX）与苯妥英钠（PHT）的药代动力学相互作用及其机制，以阐明为什么血清PHT浓度降低，尽管受损的PHT代谢能力的患者接受DOX.MethodsRats单独给予15 mg/kg的DOX或生理盐水。在DOX暴露后4天检查静脉内施用的PHT的药代动力学处置。使用肝微粒体分析CYP 2C依赖性PHTp-羟基化的酶动力学。用超滤法测定血清游离PHT浓度，并分析游离PHT浓度与血清白蛋白水平的关系。DOX组未结合的血清PHT浓度及其fu显著高于对照组，而CLtot/fu（内在清除率的测量）显著降低。即使使用白蛋白浓度等于在control group.ConclusionsDOX治疗的血清样本中观察到的增加thefu通过抑制代谢能力增加未结合的血清PHT浓度，并通过降低血清白蛋白和其亲和力改变总PHT PHT。
ObjectivesWe investigated the pharmacokinetic interaction of doxorubicin (DOX) with phenytoin (PHT) and the underlying mechanism in rats to clarify why the serum PHT concentration decreases despite the impaired PHT metabolic capacity in patients receiving DOX.MethodsRats were administered 15 mg/kg of DOX or saline alone. The pharmacokinetic disposition of intravenously administered PHT was examined 4 days after DOX exposure. Enzyme kinetics of CYP2C-dependent PHTp-hydroxylation were analysed using hepatic microsomes. The unbound PHT concentration in serum was measured by the ultrafiltration method, and the relationship between the unbound fraction (fu) and serum albumin level was assessed.Key findingsThe total clearance (CLtot) of PHT was significantly increased by DOX, but the activity of PHTp-hydroxylation conversely decreased. The unbound serum PHT concentration and itsfuwere significantly higher in the DOX group than in the control group, and the CLtot/fu, a measure of intrinsic clearance, significantly decreased. An increase in thefuwas observed even when using a serum sample with an albumin concentration equal to that in the control group.ConclusionsDOX treatment increases the unbound serum PHT concentration by depressing the metabolic capacity and alters the total PHT by reducing serum albumin and its affinity to PHT.