title: In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results.
abstract: Two different cellular assay models were assessed as in vitro systems for P-glycoprotein (P-gp) substrate identification: cellular accumulation studies with KB-V1, a human MDR1 P-gp-overexpressing multidrug-resistant human epidermoid carcinoma cell line; and transcellular transport studies with L-MDR1 (or L-mdr1a), a human MDR1 (or mouse mdr1a)-transfected porcine renal epithelial cell line. The in vitro-in vivo correlation for P-gp-mediated transport activity was also examined by comparing in vitro data obtained from L-mdr1a cell studies and in vivo data from mdr1a (-/-)/(+/+) CF-1 mice studies for several compounds. The results are summarized as follows: 1) two in vitro assay systems routinely identified the substrate for human MDR1 P-gp-mediated transport with similar quantitative results; 2) in vitro studies with L-MDR1 and L-mdr1a cells demonstrated that the P-gp substrate susceptibility is different between human and mouse for certain compounds (species difference); and 3) in vivo brain concentration ratios of mdr1a (-/-) to (+/+) CF-1 mice, either at a certain time point or up to 60 min, correlated well with the in vitro transcellular transport ratios from L-mdr1a cells (r(2) = 0.968 and 0.926, respectively). This indicates that, at least in mice, the in vitro data are valid predictors of the in vivo contribution of P-gp: the contribution of P-gp to the distribution of the compound to the brain up to 60 min post i.v. administration. These results provide a rationale for predicting in vivo relevance of P-gp in human from in vitro data using human P-gp-expressing cells.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. Masayo_Yamazaki@Merck.com
authors.forename: M
authors.initials: M
authors.lastname: Yamazaki
authors.forename: W E
authors.initials: WE
authors.lastname: Neway
authors.forename: T
authors.initials: T
authors.lastname: Ohe
authors.forename: I
authors.initials: I
authors.lastname: Chen
authors.forename: J F
authors.initials: JF
authors.lastname: Rowe
authors.forename: J H
authors.initials: JH
authors.lastname: Hochman
authors.forename: M
authors.initials: M
authors.lastname: Chiba
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D006801:Humans; D007624:KB Cells; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D013045:Species Specificity; D014407:Tumor Cells, Cultured
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004364:Pharmaceutical Preparations; C095122:multidrug resistance protein 3