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Vol. 305, Issue 1, 306-314, April 2003
Department of Biopharmaceutical Sciences, University of California,
San Francisco, California
P-Glycoprotein (P-gp) has been hypothesized to modulate intestinal drug
metabolism by increasing the exposure of drug to intracellular CYP3A
through repeated cycles of drug absorption and efflux. The rat
single-pass intestinal perfusion model was used to study this interplay
in vivo. N-Methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K77), a peptidomimetic cysteine protease inhibitor (CYP3A/P-gp substrate), and midazolam (CYP3A substrate) were each perfused through
a segment of rat ileum alone and with the P-gp inhibitor 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 (GG918). Samples were obtained continuously from the outlet
perfusate and the mesenteric vein at 5-min intervals for 40 to 60 min.
The parent drug and two main metabolites of K77 (N-desmethyl and N-oxide) and midazolam
(1-OH and 4-OH) were quantitated by liquid chromatography/mass
spectrometry. K77 appearance in the mesenteric blood
(Pblood = 5 ± 3 × 10
6 cm/s) was increased 3-fold with GG918, whereas
midazolam permeability (Pblood = 1.1 ± 0.3 × 104 cm/s) was unchanged by GG918.
K77 metabolites were preferentially excreted into the lumen, 4-OH
midazolam was found equally in lumen and blood, and 1-OH was mainly
excreted into blood. The extent of metabolism was estimated by
calculating the fraction metabolized = 1 
Pblood/Plumen and
the extraction ratio (ER) determined from the direct measurement of
known metabolites as ER = sum metabolitesall/(sum metabolitesall + drug in blood). When P-gp was inhibited,
the fraction metabolized for K77 was decreased (95 to 85%) and the ER
tended toward a decrease, whereas no differences in either parameter
were observed for midazolam (not a P-gp substrate). These data support
a role for P-gp in modulating the extent of intestinal metabolism in
vivo by controlling drug access to the enzyme.
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