TY - JOUR T1 - In Vitro Substrate Identification Studies for P-glycoprotein-Mediated Transport: Species Difference and Predictability of in Vivo Results JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 723 LP - 735 VL - 296 IS - 3 AU - Masayo Yamazaki AU - William E. Neway AU - Tomoyuki Ohe AU - I-Wu Chen AU - Janice F. Rowe AU - Jerome H. Hochman AU - Masato Chiba AU - Jiunn H. Lin Y1 - 2001/03/01 UR - http://jpet.aspetjournals.org/content/296/3/723.abstract N2 - 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 MDR1P-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 frommdr1a (−/−)/(+/+) CF-1 mice studies for several compounds. The results are summarized as follows: 1) two in vitro assay systems routinely identified the substrate for humanMDR1 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 (r2 = 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. The American Society for Pharmacology and Experimental Therapeutics ER -