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Vol. 300, Issue 3, 1036-1045, March 2002
Department of Biopharmaceutical Sciences, University of California
San Francisco, San Francisco, California
Drug efflux by intestinal P-glycoprotein (P-gp) is known to decrease
the oral bioavailability of many CYP3A4 substrates. We hypothesized
that the interplay occurring between P-gp and CYP3A4 at the apical
membrane would increase the opportunity for drug metabolism. To define
the roles of P-glycoprotein (P-gp) and CYP3A4 in controlling the extent
of intestinal absorption and metabolism, two substrates were tested.
The transport, metabolism, and intracellular levels of
N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K77, a cysteine protease inhibitor; P-gp and CYP3A4 substrate) and
felodipine (CYP3A4 substrate only) were measured across
CYP3A4-transfected Caco-2 cells in the presence of an inhibitor of
CYP3A4 and P-gp, cyclosporine (CsA), or an inhibitor of P-gp and not
CYP3A4, GG918 (N-{4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). The extent of metabolism was measured by calculating the
extraction ratio (ER) across the cells, while accounting for intracellular changes occurring with P-gp inhibition. The (A)pical to
(B)asolateral and B
A ERs for K77 were 0.33 and 0.06, respectively. These changed with GG918 to 0.14 and 0.12 and with CsA to 0.06 and
0.04. Felodipine ERs were similar in both directions, 0.26 and 0.24 (AB and BA), and were unchanged in the presence of GG918 but
decreased with CsA (0.14 and 0.11). The K77 absorption rate was
increased 5 and 4.2-fold in the presence of CsA and GG918, respectively, whereas no change was observed for felodipine absorption. The decreased AB ER and increased absorption of K77 with GG918 suggest that P-gp influences the extent of drug metabolism in the
intestine via prolonging the access of drugs to CYP3A4 near the apical
membrane and decreasing transport across the cells.
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