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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Unmasking the Dynamic Interplay between Intestinal P-Glycoprotein and CYP3A4

Carolyn L. Cummins, Wolfgang Jacobsen and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 2002, 300 (3) 1036-1045; DOI: https://doi.org/10.1124/jpet.300.3.1036
Carolyn L. Cummins
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Wolfgang Jacobsen
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Leslie Z. Benet
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Abstract

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 ofN-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 (A→B and B→A), 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 A→B 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.

Footnotes

  • ↵1 Current address: Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, CO 80262.

  • ↵2 Dr. Benet has a financial interest in and serves as Chairman of the Board of AvMax, Inc.

  • Financial support was provided by National Institutes of Health Grant CA72006 (to L.Z.B.) and Affymax Research Institute (to C.C.), as well as by an unrestricted gift from Amgen, Inc. This work was presented in part as an oral presentation at the American Society for Pharmacology and Experimental Therapeutics Meeting in Orlando, FL, March 31, 2001.

  • Abbreviations:
    P-gp
    P-glycoprotein
    CsA
    cyclosporine
    TPA
    12-O-tetradecanoylphorbol 13-acetate
    GG918
    GF120918: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
    HPLC
    high-pressure liquid chromatography
    PBS
    phosphate-buffered saline
    DMSO
    dimethyl sulfoxide
    ER
    extraction ratio
    K77
    K11777: N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl
    LC/MS
    liquid chromatography/mass spectrometry
    • Received September 6, 2001.
    • Accepted November 13, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 300 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 300, Issue 3
1 Mar 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Unmasking the Dynamic Interplay between Intestinal P-Glycoprotein and CYP3A4

Carolyn L. Cummins, Wolfgang Jacobsen and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1036-1045; DOI: https://doi.org/10.1124/jpet.300.3.1036

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Unmasking the Dynamic Interplay between Intestinal P-Glycoprotein and CYP3A4

Carolyn L. Cummins, Wolfgang Jacobsen and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 1, 2002, 300 (3) 1036-1045; DOI: https://doi.org/10.1124/jpet.300.3.1036
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