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Vol. 292, Issue 1, 310-318, January 2000
Department of Drug Metabolism, Merck Research Laboratories, West
Point, Pennsylvania
Caco-2 cells grown in the presence of 1
,25-di-OH vitamin
D3 (di-OH vit D3) were used as a model to
evaluate the effects of P-glycoprotein (Pgp) efflux on CYP3A4-mediated
metabolism of indinavir during intestinal absorption. Caco-2 cells
grown under these conditions demonstrated significant CYP3A4 activity
and maintained Pgp-mediated directional transport of indinavir.
Metabolism of indinavir in the di-OH vit D3-treated cells
correlated with the level of CYP3A activity and generated metabolites
consistent with CYP3A4-mediated metabolism. During transport
experiments, indinavir metabolites are selectively secreted into the
apical compartment, consistent with Pgp-mediated efflux. Using
formation of the most abundant metabolite, M6, as a marker for
indinavir metabolism, we observed that the extent of indinavir
metabolism is not significantly affected by the direction of indinavir
transport or by inhibition of Pgp with cyclosporin A. However, because
Pgp efflux results in higher indinavir transport in the
basolateral-to-apical direction than in the apical-to-basolateral
direction, the ratio of M6 produced normalized to the amount of drug
transported across the monolayer was higher for apical-to-basolateral
transport. Thus, Pgp efflux in a direction opposite to absorptive
transport results in more metabolite produced per mole of drug that is
absorbed. In summary, the results support a role of Pgp in increasing
intestinal presystemic metabolism and in removal of CYP3A4-generated
metabolites from the intracellular compartment.
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