TY - JOUR T1 - Kinetic Analysis of the Cooperation of P-Glycoprotein (P-gp/<em>Abcb1</em>) and Breast Cancer Resistance Protein (Bcrp/<em>Abcg2</em>) in Limiting the Brain and Testis Penetration of Erlotinib, Flavopiridol, and Mitoxantrone JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 788 LP - 796 DO - 10.1124/jpet.109.162321 VL - 333 IS - 3 AU - Hiroshi Kodaira AU - Hiroyuki Kusuhara AU - Junko Ushiki AU - Eiichi Fuse AU - Yuichi Sugiyama Y1 - 2010/06/01 UR - http://jpet.aspetjournals.org/content/333/3/788.abstract N2 - A synergistic effect of P-glycoprotein (P-gp)/Abcb1a and breast cancer resistance protein (Bcrp)/Abcg2 was reported to limit the brain penetration of their common substrates. This study investigated this based on pharmacokinetics using Mdr1a/1b(−/−), Bcrp(−/−), and Mdr1a/1b(−/−)/Bcrp(−/−) mice. Comparison of the brain- and testis-to-plasma ratios (Cbrain/Cplasma and Ctestis/Cplasma, respectively) of the reference compounds quinidine and dantrolene for P-gp and Bcrp, respectively, indicates that impairment of either P-gp and Bcrp did not cause any change in the efflux activities of Bcrp or P-gp, respectively, at both the blood-brain barrier (BBB) and blood-testis barrier (BTB). The Cbrain/Cplasma and Ctestis/Cplasma of the common substrates erlotinib, flavopiridol, and mitoxantrone were markedly increased in Mdr1a/1b(−/−)/Bcrp(−/−) mice even compared with Mdr1a/1b(−/−) and Bcrp(−/−) mice. Efflux activities by P-gp and Bcrp relative to passive diffusion at the BBB and BTB were separately evaluated based on the Cbrain/Cplasma and Ctestis/Cplasma in the knockout strains to the wild-type strain. P-gp made a larger contribution than Bcrp to the net efflux of the common substrates, but Bcrp activities were also significantly larger than passive diffusion. These parameters could reasonably account for the marked increase in Cbrain/Cplasma and Ctestis/Cplasma in the Mdr1a/1b(−/−)/Bcrp(−/−) mice. In conclusion, the synergistic effect of P-gp and Bcrp on Cbrain/Cplasma and Ctestis/Cplasma can be explained by their contribution to the net efflux at the BBB and BTB without any interaction between P-gp and Bcrp. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -