In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results
| Autor: | M, Yamazaki, W E, Neway, T, Ohe, I, Chen, J F, Rowe, J H, Hochman, M, Chiba, J H, Lin |
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| Rok vydání: | 2001 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B Reproducibility of Results Biological Transport Models Biological KB Cells Mice Pharmaceutical Preparations Species Specificity Predictive Value of Tests Tumor Cells Cultured Animals Humans ATP-Binding Cassette Transporters ATP Binding Cassette Transporter Subfamily B Member 1 |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 296(3) |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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