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Vol. 296, Issue 3, 723-735, March 2001
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
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
(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.
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