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Vol. 30, Issue 4, 457-463, April 2002
Department of Pharmaceutics, School of Pharmacy, Rutgers
University, Piscataway, New Jersey
Multidrug resistance conferred to cancer cells is often mediated by
the expression of efflux transporter "pumps". It is also believed
that many of the same transporters are involved in drug efflux from
numerous normal endothelial and epithelial cell types in the intestine,
brain, kidney, and liver. Etoposide transport kinetics were
characterized in Caco-2 cells and in well established Madin-Darby
canine kidney (MDCKII) cell lines that were stably-transfected with a human cDNA encoding P-glycoprotein (Pgp), human multidrug resistance protein (MRP1), or the canalicular multispecific organic anion (cMOAT) transporters to determine the roles of these transporters in etoposide efflux. Etoposide transport kinetics were
concentration-dependent in the MDCKII-MDR1 and MDCKII-cMOAT cells. The
apparent secretory Michaelis constant (Km)
and carrier-mediated permeability (Pc) values for Pgp and cMOAT were 254.96 ± 94.39 µM and 5.96 ± 0.41 × 10
6 cm/s and 616.54 ± 163.15 µM
and 1.87 ± 0.10 × 105 cm/s, respectively. The
secretory permeability of etoposide decreased significantly in the
basal to apical (B to A) (i.e., efflux) direction, whereas the
permeability increased 2.3-fold in the apical to basal (A to B)
direction in MDCKII-MDR1 cells in the presence of elacridar (GF120918). Moderate inhibition of etoposide efflux by
leukotriene C4 (LTC4) was observed in
MDCKII-cMOAT cells. Furthermore, etoposide inhibited LTC4
efflux, confirming the involvement of cMOAT. The flux of etoposide in
MDCKII-MRP1 cells was similar to that in MDCKII/wt control cells. The
current results demonstrate that the secretory transport mechanism of
etoposide involves multiple transporters, including Pgp and cMOAT but
not MRP1. These results demonstrate that Pgp and cMOAT are involved in
the intestinal secretory transport of etoposide. Since the intestinal
secretion of etoposide was previously reported in the literature, it
also suggests that they may be involved in the in vivo intestinal
secretion of etoposide; however, mechanistic in vivo studies are
required to confirm this.
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