In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results.
Article Details
- CitationCopy to clipboard
Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, Chiba M, Lin JH
In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results.
J Pharmacol Exp Ther. 2001 Mar;296(3):723-35.
- PubMed ID
- 11181899 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Diazepam P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Digoxin P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Indinavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Ketazolam P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Progesterone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Ritonavir P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Vinblastine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails