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

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 (1/1) mice received a 4-h constant-rate i.v. infusion (2 mg/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 concentra-tions. Mdr1a (–/–) mice exhibited increased SDZ PSC 833 ac-cumulation in cerebrum, cerebellum and somewhat in testes and small intestine compared with the wild-type mice. The difference between mdr1a (–/–) and (1/1) brain (cerebrum and cerebellum) penetration depended on SDZ PSC 833 blood concentrations, because this cyclosporin analog apparentl