Vol. 285, Issue 2, 438-443, May 1998

Effect of the Mdr1a P-Glycoprotein Gene Disruption on the Tissue Distribution of SDZ PSC 833, a Multidrug Resistance-Reversing Agent, in Mice

S. Desrayaud , E. C. M. De Lange, M. Lemaire, A. Bruelisauer, A. G. De Boer and D. D. Breimer

Drug Metabolism and Pharmacokinetics, CFSS, Novartis Pharma A.G., CH-4002 Basel, Switzerland (S.D., M.L., A.B.), INSERM U26, Hôpital Fernand Widal, 75010 Paris, France (S.D.) and Leiden/Amsterdam Center for Drug Research (LACDR), Division of Pharmacology, Sylvius Laboratories, 2300 RA Leiden, The Netherlands (E.C.M.DeL., A.G.DeB., D.D.B.)

The involvement of mdr1a P-glycoprotein (P-gP) on the tissue distribution of the multidrug resistance-reversing agent SDZ PSC 833 was assessed by use of mdr1a (-/-) mice. The mdr1a (-/-) and wild-type mdr1a (+/+) mice received a 4-h constant-rate i.v. infusion (2 µg/min) of [¹⁴C]SDZ PSC 833. Mice were sacrificed at 0, 0.5, 1, 2 and 4 h during infusion and at 0.5, 1, 3, 8 and 24 h after stopping the infusion. Blood and tissues were analyzed on total (¹⁴C) and parental SDZ PSC 833 concentrations. Mdr1a (-/-) mice exhibited increased SDZ PSC 833 accumulation in cerebrum, cerebellum and somewhat in testes and small intestine compared with the wild-type mice. The difference between mdr1a (-/-) and (+/+) brain (cerebrum and cerebellum) penetration depended on SDZ PSC 833 blood concentrations, because this cyclosporin analog apparently governs its own brain penetration by inhibiting the P-glycoprotein pump in mdr1a (+/+) mice. Thus the mdr1a (-/-)/(+/+) ratio of brain concentrations tended to decrease and increase at high and low blood concentrations, respectively. These findings clearly demonstrate the interaction of SDZ PSC 833 with the P-glycoprotein present at the blood-brain barrier. The SDZ PSC 833 distribution in other mdr1a P-glycoprotein-expressed tissues, as well as its metabolism and elimination, was not affected by the mdr1a gene disruption. This suggests that factors other than mdr1a P-gP are involved in the disposition of this multidrug resistance-reversing agent.