Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds

• Published in: Pharmaceutical research 2001-07, Vol.18 (7), p.957-963
• Main Authors: DAGENAIS, Claude, JIAN ZONG, DUCHARME, Julie, POLLACK, Gary M
• Format: Article
• Language: English
• Subjects: Anesthetics. Neuromuscular blocking agents; Animals; Antiarythmic agents; Antimalarials - blood; Antimalarials - pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B - deficiency; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - pharmacokinetics; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - pharmacokinetics; Biological and medical sciences; Blood-brain barrier; Blood-Brain Barrier - genetics; Brain - metabolism; Brain research; Calcium Channel Blockers - blood; Calcium Channel Blockers - pharmacokinetics; Cardiovascular system; Dose-Response Relationship, Drug; Female; Gender differences; Glycoproteins; Laboratory animals; Male; Medical sciences; Mice; Mice, Knockout; Morphine; Morphine - blood; Morphine - pharmacokinetics; Narcotics - blood; Narcotics - pharmacokinetics; Neuropharmacology; Perfusion - methods; Pharmacology. Drug treatments; Plasma; Quinidine - blood; Quinidine - pharmacokinetics; Sex Characteristics; Substrate Specificity - genetics; Verapamil - blood; Verapamil - pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1010984110732

This study assessed the influence of mdr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Clup) of morphine, quinidine and verapamil. Clup of radiolabeled substrates was determined in P-gp-competent and deficient [mdr1a(-/-)] mice by in situ brain perfusion. Brain:plasma distribution of substrates after i.v. administration was determined in both strains. Genetic disruption of mdr1a P-gp resulted in 1.3-, 6.6- and 14-fold increases in Clup for morphine, verapamil and quinidine, respectively. With the exception of small differences for verapamil, gender did not affect Clup. Saturable transport of verapamil and quinidine was observed only in P-gp-competent mice, with apparent IC50 values for efflux of 8.6 +/- 2.3 microM and 36 +/- 2 microM, respectively. Verapamil Clup was approximately 50% higher in mdr1a(+/-) vs. mdr1a(+/+) mice; no such difference was observed for quinidine. In P-gp-competent mice, uptake of verapamil and quinidine was unaffected by organic vehicles. Plasma decreased VER Clup to a greater extent in the presence of P-gp. The influence of P-gp in situ was lower than, but correlated with, the effect in vivo. P-gp decreases Clup of morphine, verapamil and quinidine in situ with little or no influence of gender, but this effect cannot fully account for the effects of P-gp in vivo. P-gp is the only saturable transport mechanism for verapamil and quinidine at the murine blood-brain barrier. The influence of protein binding on Clup may be enhanced by P-gp-mediated efflux.