Nadai M, Hasegawa T, Wang L, Tagaya O, Nabeshima T
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Drug Metab Dispos. 1994 Jul-Aug;22(4):561-5.
Mutant rats possessing conjugated hyperbilirubinemia have recently been established from Sprague-Dawley rats (SDRs) and are called Eisai hyperbilirubinemic rats (EHBRs). The effects of hyperbilirubinemia on the disposition, renal handling, and protein binding behavior of enprofylline, which is mainly excreted into the urine by an active tubular secretion mechanism, were investigated in 9- and 19-week-old EHBRs and compared with their age-matched normal SDRs. Enprofylline was administered intravenously at a dose of 2.5 mg/kg, which exhibits linear kinetics. Pharmacokinetic parameters for both total and unbound enprofylline were estimated by model-independent methods. Both systemic clearance and volume of distribution at steady state of enprofylline significantly increased in 19-week-old EHBRs. However, there were no differences in the glomerular filtration rate estimated as inulin clearance and fraction of urinary excretion as unchanged drug between EHBRs and normal SDRs. Significant decreases in both the binding capacity and number of binding sites were observed in 19-week-old EHBRs, but no such changes were observed between 9-week-old EHBRs and SDRs. Hyperbilirubinemia in EHBRs had no effect on the pharmacokinetics and renal handling of unbound enprofylline. These results indicate that the pharmacokinetics of enprofylline, but not renal handling, glomerular filtration, or tubular secretion are modified in EHBRs by changes in protein binding behavior.
最近从斯普拉格-道利大鼠（SDRs）培育出了患有结合性高胆红素血症的突变大鼠，称为卫材高胆红素血症大鼠（EHBRs）。研究了高胆红素血症对恩丙茶碱处置、肾脏处理及蛋白结合行为的影响，恩丙茶碱主要通过肾小管主动分泌机制排泄到尿液中，研究对象为9周龄和19周龄的EHBRs，并与年龄匹配的正常SDRs进行比较。以2.5mg/kg的剂量静脉注射恩丙茶碱，该剂量呈现线性动力学。通过非模型依赖方法估算总恩丙茶碱和游离恩丙茶碱的药代动力学参数。19周龄的EHBRs中，恩丙茶碱的全身清除率和稳态分布容积均显著增加。然而，EHBRs和正常SDRs之间，以菊粉清除率估算的肾小球滤过率及未变化药物的尿排泄分数并无差异。在19周龄的EHBRs中观察到结合能力和结合位点数量均显著降低，但在9周龄的EHBRs和SDRs之间未观察到此类变化。EHBRs中的高胆红素血症对游离恩丙茶碱的药代动力学和肾脏处理无影响。这些结果表明，EHBRs中恩丙茶碱的药代动力学因蛋白结合行为的改变而发生改变，但肾脏处理、肾小球滤过或肾小管分泌未受影响。
