Kwei G Y, Alvaro R F, Chen Q, Jenkins H J, Hop C E, Keohane C A, Ly V T, Strauss J R, Wang R W, Wang Z, Pippert T R, Umbenhauer D R
Departments of Drug Metabolism and Safety Assessment, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Drug Metab Dispos. 1999 May;27(5):581-7.
The pharmacokinetics and hepatic metabolism of [3H] ivermectin (IVM) and [3H]cyclosporin A (CSA) were investigated in a subpopulation of the CF-1 mouse stock naturally deficient in mdr1a p-glycoprotein (PGP). A survey of key drug-metabolizing activities in liver fractions from PGP-deficient (-/-) or wild-type (+/+) animals indicated the two subpopulations are not different in hepatic metabolic activity and capacity. Intravenous pharmacokinetics of CSA were identical between the two groups, and results from microsomal incubations indicated similar biotransformation of IVM and CSA in liver. Intestinal excretion of [3H]IVM and [3H]CSA was enhanced in PGP (+/+) animals. Absence of PGP resulted in higher blood concentrations of IVM after oral dosing, suggesting enhanced absorption of IVM in (-/-) mice. Concentrations of [3H]IVM and [3H]CSA were always greater in the brains of (-/-) mice compared with (+/+) mice after either i.v. or oral administration. In contrast, liver concentrations of either compound were not different between (+/+) and (-/-) animals after an i.v. dose. These results show the PGP (-/-) and (+/+) subpopulations of CF-1 mice are useful for studying the role of mdr1a PGP in systemic exposure and tissue disposition of PGP substrates in the absence of metabolism differences.
在自然缺乏mdr1a P-糖蛋白（PGP）的CF-1小鼠种群亚群中，研究了[3H]伊维菌素（IVM）和[3H]环孢素A（CSA）的药代动力学及肝脏代谢情况。对PGP缺陷型（-/-）或野生型（+/+）动物肝脏组分中关键药物代谢活性的调查表明，这两个亚群在肝脏代谢活性和能力方面并无差异。两组间CSA的静脉药代动力学相同，微粒体孵育结果表明肝脏中IVM和CSA的生物转化相似。PGP（+/+）动物中[3H]IVM和[3H]CSA的肠道排泄增强。PGP缺失导致口服给药后IVM的血药浓度更高，表明（-/-）小鼠中IVM的吸收增强。静脉注射或口服给药后，（-/-）小鼠脑中[3H]IVM和[3H]CSA的浓度始终高于（+/+）小鼠。相比之下，静脉给药后，（+/+）和（-/-）动物中两种化合物的肝脏浓度并无差异。这些结果表明，在不存在代谢差异的情况下，CF-1小鼠的PGP（-/-）和（+/+）亚群可用于研究mdr1a PGP在PGP底物全身暴露和组织分布中的作用。
