Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.

Abstract

We have previously shown that absence of the mouse mdrla (also called mdr3) P-glycoprotein in mdrla ( -/-) "knockout" mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds. We show here that the mouse mdrla and the human MDR1 P-glycoprotein actively transport ivermectin, dexamethasone, digoxin, and cyclosporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radiolabeled drugs in mdrla ( -/-) and wild-type mice resulted in markedly (20-to 50-fold) higher levels of radioactivity in mdrla (-/-) brain for digoxin and cyclosporin A, with more moderate effects for dexamethasone (2-to 3-fold) and morphine (1.7-fold). Digoxin and cyclosporin A were also more slowly eliminated from mdrla (-/-) mice. Our findings show that P-glycoprotein can be a major determinant for the pharmacology of several medically important drugs other than anti-cancer agents, especially in the blood-brain barrier. These results may explain a range of pharmacological interactions observed between various drugs in patients. (J. Clin. Invest. 1995.96:1698-1705

Penetration of Amitriptyline, but Not of Fluoxetine, into Brain is Enhanced in Mice with Blood-Brain Barrier Deficiency Due to Mdr1a P-Glycoprotein Gene Disruption

“…The tissue distribution of AMI and its metabolites in mdr1a Ϫ/Ϫ and mdr1a ϩ/ϩ mice is equivalent to that which has been described for other substrates of the same gene product (Schinkel et al 1995b;Schinkel 1998;Tsuji and Tamai 1997).…”

“…This was demonstrated by a cerebrum:spleen ratio and a metencephalon:spleen ratio that was two to four times higher in mdr1a Ϫ/Ϫ mice than in ϩ/ϩ control mice. It is very unlikely that the uptake of these substances into the spleen is influenced by P-glycoprotein because P-glycoprotein expression is low in this organ (Thiebaut et al 1987;Cordon-Cardo et al 1989, and in substrate distribution experiments only a few differences are recordable between the ϩ/ϩ animals and the Ϫ/Ϫ mutants (Schinkel et al 1994(Schinkel et al , 1995b. Our results support the notion that the penetration of AMI and its metabolites into cerebrum and metencephalon is enhanced in mutants that lack P-glycoprotein, as compared to control mice, where P-glycoprotein is located in the endothelial cells of the brain capillaries.…”

Vasopressin Mediates the Response of the Combined Dexamethasone/CRH Test in Hyper-anxious Rats Implications for Pathogenesis of Affective Disorders

“…Receptor occupancy by endogenous glucocorticoids at the pituitary, which is known to be the preferred site of DEX action (Schinkel et al 1995;de Kloet et al 1998;Meijer et al 1998), is minimal during the diurnal trough. Thus, a maximal effect is achieved by administering DEX at 12 M, when the endogenous HPA system activity is minimal (Krieger 1979;Hatzinger et al 1996).…”

Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport

“…Polarized canine (MDCKII) or porcine (LLC-PK1) kidney-cell lines stably expressing MDR1, MRP1, or MRP2 (cMOAT) have been described before (Schinkel et al, 1995;Evers et al, 1997;Bakos et al, 1998). MDCKII-derived cell lines were cultured in DMEM with 10% fetal calf serum, LLC-PK1-derived cell lines in Medium 199 with 10% fetal calf serum.…”

“…Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1-and MRP2-mediated transport Recently, we established two model systems suitable for testing inhibitors of MDR1 Pgp, MRP1 and MRP2: i) A set of polarized cell lines stably expressing MDR1, MRP1, or MRP2 cDNA (Schinkel et al, 1995;Evers et al, 1996;. In these cells MDR1 Pgp and MRP2 are localized in the apical plasma membrane, whereas MRP1 is localized in the lateral plasma membrane.…”