Disposition of ivermectin and cyclosporin A in CF-1 mice deficient in mdr1a P-glycoprotein.

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.

[1]  M Rowland,et al.  Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine , 1995, Clinical pharmacology and therapeutics.

[2]  J. Kolars,et al.  First-pass metabolism of cyclosporin by the gut , 1991, The Lancet.

[3]  W B Jakoby,et al.  Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. , 1974, The Journal of biological chemistry.

[4]  J. Beijnen,et al.  Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[5]  F. Loor,et al.  Decreased biotolerability for ivermectin and cyclosporin a in mice exposed to potent P‐glycoprotein inhibitors , 1995, International journal of cancer.

[6]  Y. Tanigawara,et al.  Human P-glycoprotein transports cyclosporin A and FK506. , 1993, The Journal of biological chemistry.

[7]  P. Watkins,et al.  The barrier function of CYP3A4 and P-glycoprotein in the small bowel. , 1997, Advanced drug delivery reviews.

[8]  E. Schuetz,et al.  Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. , 1996, Molecular pharmacology.

[9]  G R Lankas,et al.  P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. , 1997, Toxicology and applied pharmacology.

[10]  G. Giaccone,et al.  A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  J. H. Beijnen,et al.  Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs , 1994, Cell.

[12]  L. Benet,et al.  Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy , 1995, Molecular carcinogenesis.

[13]  M. Brecher,et al.  Cremophor-EL enhances taxol efficacy in a multi-drug resistant C1300 neuroblastoma cell line. , 1993, Anticancer research.

[14]  G R Lankas,et al.  Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism. , 1997, Toxicology and applied pharmacology.

[15]  B. Beltz,et al.  Immunocytochemical Techniques: Principles and Practice , 1989 .

[16]  M. Millward,et al.  Measurement of cremophor EL following taxol: plasma levels sufficient to reverse drug exclusion mediated by the multidrug-resistant phenotype. , 1993, Journal of the National Cancer Institute.

[17]  J. Beijnen,et al.  Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. , 1997, British Journal of Cancer.

[18]  D. Waxman,et al.  Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. , 1986, The Journal of biological chemistry.

[19]  T. Omura,et al.  THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. , 1964, The Journal of biological chemistry.

[20]  P. Borst,et al.  Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. , 1995, The Journal of clinical investigation.

[21]  A. Y. Lu,et al.  Human cytochrome P450 3A4-catalyzed testosterone 6 beta-hydroxylation and erythromycin N-demethylation. Competition during catalysis. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[22]  G R Lankas,et al.  Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. , 1998, Reproductive toxicology.

[23]  M. Relling,et al.  P-glycoprotein: a major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. , 1996, Proceedings of the National Academy of Sciences of the United States of America.