Disposition of Ivermectin and Cyclosporin A in CF-1 Mice Deficient in mdr1a P-Glycoprotein

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Vol. 27, Issue 5, 581-587, May 1999

Disposition of Ivermectin and Cyclosporin A in CF-1 Mice Deficient in mdr1a P-Glycoprotein

G. Y. Kwei, R. F. Alvaro, Q. Chen, H. J. Jenkins, C. E. A. C. Hop, C. A. Keohane, V. T. Ly, J. R. Strauss, R. W. Wang, Z. Wang, T. R. Pippert,¹ and D. R. Umbenhauer¹

Departments of Drug Metabolism and Safety Assessment, Merck Research Laboratories, Rahway, New Jersey

The pharmacokinetics and hepatic metabolism of [³H] ivermectin (IVM) and [³H]cyclosporin A (CSA) were investigated in a subpopulation ofthe CF-1 mouse stock naturally deficient in mdr1a p-glycoprotein(PGP). A survey of key drug-metabolizing activities in liver fractionsfrom PGP-deficient ( $-$ / $-$ ) or wild-type (+/+) animals indicatedthe two subpopulations are not different in hepatic metabolicactivity and capacity. Intravenous pharmacokinetics of CSA wereidentical between the two groups, and results from microsomalincubations indicated similar biotransformation of IVM and CSAin liver. Intestinal excretion of [³H]IVM and [³H]CSA was enhanced in PGP (+/+) animals. Absence of PGP resultedin higher blood concentrations of IVM after oral dosing, suggestingenhanced absorption of IVM in ( $-$ / $-$ ) mice. Concentrations of [³H]IVM and [³H]CSA were always greater in the brains of ( $-$ / $-$ ) mice comparedwith (+/+) 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 showthe PGP ( $-$ / $-$ ) and (+/+) subpopulations of CF-1 mice are usefulfor studying the role of mdr1a PGP in systemic exposure and tissuedisposition of PGP substrates in the absence of metabolismdifferences.

¹ Current affiliation: Department of Safety Assessment, Merck Research Laboratories, West Point,PA.

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