Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner.
Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner.
复制标题
Cyclosporine 以时间依赖性方式抑制大鼠肝细胞色素 P450。
DOI：
10.1046/j.1523-1755.1998.00970.x
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Koop,DR
中科院分区：
文献类型：
--
作者：
Brunner,LJ;Bennett,WM;Koop,DR
环孢素抑制大鼠肝细胞色素P450在一个时间依赖性mathematics.BackgroundCyclosporine是一种有效的免疫抑制剂，已知选择性抑制特定的细胞色素P450（P450）亚型慢性治疗大鼠。环孢素在大鼠中经历显著的肝脏代谢，主要是由于P450 3A亚型。因此，环孢素肝代谢的改变可能导致药物药代动力学或药效学的变化。本研究的目的是研究慢性环孢素给药对P450蛋白表达和代谢活性在大鼠模型的慢性环孢素nephropathy.MethodsAdult雄性大鼠环孢素15毫克/公斤/天或车辆1毫升/公斤/天皮下注射长达28天的时间效应。为了检查药物去除后代谢活性是否恢复，对另外的大鼠给予环孢菌素28天，然后再给予溶剂至多15天。肝P450蛋白表达和微粒体代谢活性测定通过Western印迹分析andin vitrosteroid hydroxylation，respectively. Results环孢素谷水平逐步增加，在28天的时间内，仍然是可测量的长达15天后停止。免疫印迹分析表明，慢性环孢素治疗抑制P450 3A 2的表达和体外类固醇羟基化的时间依赖性的方式。15天后停止环孢素给药，肝代谢活性和微粒体P450 3A 2水平恢复到接近pre-dosing levels.ConclusionsWe的结论是，时间依赖性的P450抑制环孢素可能至少部分解释环孢素药代动力学的变异。这些研究支持以下假设：在大鼠慢性给药期间，除P450 3A 2外的肝脏亚型可能负责环孢霉素代谢。
Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner.BackgroundCyclosporine is a potent immunosuppressant known to selectively suppress specific cytochrome P450 (P450) isoforms following chronic therapy in the rat. Cyclosporine undergoes significant hepatic metabolism in the rat, primarily due to P450 3A isoforms. Hence, alterations in hepatic metabolism of cyclosporine may lead to changes in drug pharmacokinetics or pharmacodynamics. The purpose of this study was to examine the temporal effect of chronic cyclosporine dosing on P450 protein expression and metabolic activity in a rat model of chronic cyclosporine nephropathy.MethodsAdult male rats were administered cyclosporine 15 mg/kg/day or vehicle 1 ml/kg/day by subcutaneous injection for up to 28 days. To examine whether or not metabolic activity recovered following drug removal, additional rats were administered cyclosporine for 28 days followed by vehicle for up to an additional 15 days. Hepatic P450 protein expression and microsomal metabolic activity were measured by Western blot analysis andin vitrosteroid hydroxylation, respectively.ResultsCyclosporine trough levels progressively increased over the 28 days period and were still measurable for up to 15 days after discontinuation. Immunoblot analysis indicated that chronic cyclosporine treatment suppressed P450 3A2 expression andin vitrosteroid hydroxylation in a time-dependent manner. Fifteen days following discontinuation of cyclosporine dosing, hepatic metabolic activity and microsomal P450 3A2 levels returned to near pre-dosing levels.ConclusionsWe conclude that the time-dependent P450 suppression by cyclosporine may at least partially explain the variability in cyclosporine pharmacokinetics. These studies support the hypothesis that hepatic isoforms other than P450 3A2 may be responsible for cyclosporine metabolism during chronic treatment in the rat.