In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results.
J Pharmacol Exp Ther
; 296(3): 723-35, 2001 Mar.
Article
in En
| MEDLINE
| ID: mdl-11181899
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pharmaceutical Preparations
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Pharmacol Exp Ther
Year:
2001
Document type:
Article
Affiliation country:
United States