AAPS PharmSci

, Volume 1, Issue 4, pp 14–19 | Cite as

Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P 4503A4

  • Meguru Achira
  • Kiyomi Ito
  • Hiroshi Suzuki
  • Yuichi SugiyamaEmail author


It has been suggested that cytochrome P450 3A4 (CYP3A4) and MDR1 P-glycoprotein (P-gp) act synergistically to limit the bioavailability of orally administered agents. In order to determine the relative role of these proteins, it is essential to identify a selective inhibitor for either P-gp or CYP3A4. In the present investigation, comparative studies were performed to examine the effect of inhibitors on the function of these proteins. The IC50 of P-gp function, determined by examining the inhibition of the transcellular transport of vinblastine across Caco-2 monolayers, was in the order PSC833 ≪ ketoconazole, verapamil ≪ N-(2(R)-hydroxy-1(S)-indanyl)-5-(2(S)-(1,1-dimethylethylaminocarbonyl)-4-(furo(2,3-b)pyridin-5-yl) methyl)piperazin-1-yl)-4(S)-hydroxy-2(R)-phenylmethylpentanamide (L-754,394). In contrast, the IC50 of CYP3A4 function, determined by examining the inhibition of the metabolism of midazolam by intestinal and liver microsomes, was in the order L-754,384 ≪ketoconazole≪ PSC 833 and verapamil. The ratio of IC50 for P-gp to that for CYP3A4 was more than 200 for L-754,394,60 ∼ 150 for ketoconazole, 1.5 for verapamil, and 0.05 for PSC 833. Collectively, it was demonstrated that PSC 833 and L-754,394 can be used as selective inhibitors of P-gp and CYP3A4, respectively.


Verapamil Midazolam Ketoconazole Liver Microsome Oral Bioavailability 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Wacher VJ, Wu C-Y, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog. 1995;13:129–134.PubMedCrossRefGoogle Scholar
  2. 2.
    Kolars JC, Awni WM, Merion RM, Watkins PB. First-pass metabolism of cyclosporine by the gut. Lancet. 1991;338:1488–1490.PubMedCrossRefGoogle Scholar
  3. 3.
    Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther. 1992;52:453–457.PubMedCrossRefGoogle Scholar
  4. 4.
    Wu CY, Benet LZ, Hebert MF, Gupta SK, Rowland M, Gomez DY, Wacher VJ. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther. 1995;58:492–497.PubMedCrossRefGoogle Scholar
  5. 5.
    Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, McVicar JP, Barr DM, Gillies BS, Thummel KE. First-pass metabolism of midazolam by the human intestine. Clin Pharmacol Ther. 1996;60:14–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Wacher VJ, Silverman JA, Zhang Y, Benet LZ. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci. 1998;87:1322–1330.PubMedCrossRefGoogle Scholar
  7. 7.
    Sparrenboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DKF, Borst P, Nooijen WJ, Beijnen, JH, van Tellingen O. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A. 1997;94:2031–2035.CrossRefGoogle Scholar
  8. 8.
    Schinkel AH, Mayer U, Wagenaar E, Mol CAAM, van Deemter L, Smit JJM, van der Valk MA, Voordouw AC, Spits H, van Tellingen O, Zijlmans JMJM, Fibbe WE, Borst P. Normal viability and altered pharmacokinetis in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA. 1999;94:4028–4033.CrossRefGoogle Scholar
  9. 9.
    Floren LC, Bekersky I, Benet LZ, Mekki Q, Diessler D, Lee JW, Roberts JP, Hebert MF. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther. 1997;62:41–49.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang Y, Hsieh Y, Izumi T, Lin ET, Benet LZ. Effects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats. J Pharmacol Exp Ther. 1998;287:246–252.PubMedGoogle Scholar
  11. 11.
    Ito H, Kusuhara H, Sugiyama Y. Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption: theoretical approach. Pharm Res. 1999;16:225–231.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 1999

Authors and Affiliations

  • Meguru Achira
    • 1
  • Kiyomi Ito
    • 1
  • Hiroshi Suzuki
    • 1
    • 2
  • Yuichi Sugiyama
    • 1
    • 2
    Email author
  1. 1.Graduate School of Pharmaceutical SciencesThe University of TokyoTokyoJapan
  2. 2.CREST, Japan Science and Technology CorporationJapan

Personalised recommendations