Skip to main content
Log in

Effects of furanocoumarins in Kampo extract-based medicines on rat intestinal absorption of CYP3A and P-glycoprotein substrate drugs in vivo

  • Research Articles
  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

While a great deal of information of drug-drug interactions is known, most concern Western drugs. Relatively little is known of the interactions between Western drugs and traditional drugs such as Kampo extract medicines (Japanese medicines modified from traditional Chinese medicines). This study investigated the effects of the marketed Kampo extract medicines, Senkyu-cha-cho-san and Sokei-kakketsu-to, on the intestinal absorption of CYP or P-glycoprotein (P-gp) in vivo. Midazolam, a CYP3A substrate drug, or talinolol, a P-gp substrate drug, was orally administered to rats with each of these Kampo extract medicines. Senkyu-cha-chosan or Sokei-kakketsu-to administered as a standard regimen did not obviously affect Cmax and area under the curve (AUC) of midazolam, although both Kampo extract medicines contained notopterol, a potent CYP3A4 inhibitor in vitro. The results implied a lack of potent drug-drug interactions between both Kampo extract medicines and CYP3A substrate drugs. Concomitant administration of each Kampo extract medicine unexpectedly showed the tendency to decrease Cmax and AUC of talinolol. Decreased intestinal absorption of talinolol might be caused, not by the inhibition of P-gp, but by the inhibition of organic anion transporting peptides by both Kampo extract medicines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Benet, L. Z., Cummins, C. L., and Wu, C. Y., Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int. J. Pharm., 277, 3–9 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Cordon-Cardo, C., O’Brien, J. P., Casals, D., Rittman-Grauer, L., Biedler, J. L., Melamed, M. R., and Bertino, J. R., Multidrug-resistance gene (P-glycoprotein) is expressed by en dothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. U. S. A., 86, 695–698 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Cordon-Cardo, C., O’Brien, J. P., Boccia, J., Casals, D., Bertino, J. R., and Melamed, M. R., Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem., 38, 1277–1287 (1990).

    Article  PubMed  CAS  Google Scholar 

  • de Castro, W. V., Mertens-Talcott, S., Derendorf, H., and Butterweck, V., Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J. Pharm. Sci., 96, 2808–2817 (2007).

    Article  PubMed  Google Scholar 

  • Dresser, G. K., Bailey, D. G., Leake, B. F., Schwarz, U. I., Dawson, P. A., Freeman, D. J., and Kim, R. B., Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin. Pharmacol. Ther., 71, 11–20 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Englund, G., Rorsman, F., Rönnblom, A., Karlbom, U., Lazorova, L., Gråsjö, J., Kindmark, A., and Artursson, P., Regional levels of drug transporters along the human intestinal tract: co-expression of ABC and SLC transporters and comparison with Caco-2 cells. Eur. J. Pharm. Sci., 29, 269–277 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Guo, L. Q., Fukuda, K., Ohta, T., and Yamazoe, Y., Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. Drug Metab. Dispos., 28, 766–771 (2000a).

    PubMed  CAS  Google Scholar 

  • Guo, L. Q., Taniguchi, M., Xiao, Y. Q., Baba, K., Ohta, T., and Yamazoe, Y., Inhibitory effect of natural furanocoumarins on human microsomal cytochrome P450 3A activity. Jpn. J. Pharmacol., 82, 122–129 (2000b).

    Article  PubMed  CAS  Google Scholar 

  • Iwanaga, K., Hayashi, M., Hamahata, Y., Miyazaki, M., Shibano, M., Taniguchi, M., Baba, K., and Kakemi, M., Furanocoumarin derivatives in Kampo extract medicines inhibit cytochrome P450 3A4 and P-glycoprotein. Drug Metab. Dispos., 38, 1286–1294 (2010a).

    Article  PubMed  CAS  Google Scholar 

  • Iwanaga, K., Sumizawa, T., Miyazaki, M., and Kakemi, M., Characterization of organogel as a novel oral controlled release formulation for lipophilic compounds. Int. J. Pharm., 388, 123–128 (2010b).

    Article  PubMed  CAS  Google Scholar 

  • Iwanaga, K., Yoneda, S., Hamahata, Y., Miyazaki, M., Shibano, M., Taniguchi, M., Baba, K., and Kakemi, M., Inhibitory effects of furanocoumarin derivatives in Kampo extract medicines on P-glycoprotein at the blood-brain barrier. Biol. Pharm. Bull., 34, 1246–1251 (2011).

    Article  PubMed  CAS  Google Scholar 

  • Kageyama, M., Namiki, H., Fukushima, H., Ito, Y., Shibata, N., and Takada, K., In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats. Biol. Pharm. Bull., 28, 316–322 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Kakar, S. M., Paine, M. F., Stewart, P. W., and Watkins, P. B., 6″-Dihydroxybergamottin contributes to the grapefruit juice effect. Clin. Pharmacol. Ther., 75, 569–579 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Kanazu, T., Okamura, N., Yamaguchi, Y., Baba, T., and Koike, M., Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug-drug interaction model rats. Xenobiotica, 35, 305–317 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Kato, Y., Miyazaki, T., Kano, T., Sugiura, T., Kubo, Y., and Tsuji, A., Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol. J. Pharm. Sci., 98, 2529–2539 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Kono, T., Kanematsu, T., and Kitajima, M., Exodus of Kampo, traditional Japanese medicine, from the complementary and alternative medicines: is it time yet? Surgery, 146, 837–840 (2009).

    Article  PubMed  Google Scholar 

  • Lemma, G. L., Wang, Z., Hamman, M. A., Zaheer, N. A., Gorski, J. C., and Hall, S. D., The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates. Clin. Pharmacol. Ther., 79, 218–230 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Meier, Y., Eloranta, J. J., Darimont, J., Ismair, M. G., Hiller, C., Fried, M., Kullak-Ublick, G. A., and Vavricka, S. R., Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab. Dispos., 35, 590–594 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Paine, M. F., Widmer, W. W., Hart, H. L., Pusek, S. N., Beavers, K. L., Criss, A. B., Brown, S. S., Thomas, B. F., and Watkins, P. B., A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am. J. Clin. Nutr., 83, 1097–1105 (2006).

    PubMed  CAS  Google Scholar 

  • Riegelman, S. and Collier, P., The application of statistical moment theory to the evaluation of in vivo dissolution time and absorption time. J. Pharmacokinet. Biopharm., 8, 509–534 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Schmiedlin-Ren, P., Edwards, D. J., Fitzsimmons, M. E., He, K., Lown, K. S., Woster, P. M., Rahman, A., Thummel, K. E., Fisher, J. M., Hollenberg, P. F., and Watkins, P. B., Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab. Dispos., 25, 1228–1233 (1997).

    PubMed  CAS  Google Scholar 

  • Schwarz, U. I., Gramatté, T., Krappweis, J., Oertel, R., and Kirch, W., P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans. Int. J. Clin. Pharmacol. Ther., 38, 161–167 (2000).

    PubMed  CAS  Google Scholar 

  • Schwarz, U. I., Seemann, D., Oertel, R., Miehlke, S., Kuhlisch, E., Fromm, M. F., Kim, R. B., Bailey, D. G., and Kirch, W., Grapefruit juice ingestion significantly reduces talinolol bioavailability. Clin. Pharmacol. Ther., 77, 291–301 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Shirasaka, Y., Li, Y., Shibue, Y., Kuraoka, E., Spahn-Langguth, H., Kato, Y., Langguth, P., and Tamai, I., Concentration-dependent effect of naringin on intestinal absorption of beta(1)-adrenoceptor antagonist talinolol mediated by pglycoprotein and organic anion transporting polypeptide (Oatp). Pharm. Res., 26, 560–567 (2009).

    Article  PubMed  CAS  Google Scholar 

  • Shirasaka, Y., Kuraoka, E., Spahn-Langguth, H., Nakanishi, T., Langguth, P., and Tamai, I., Species difference in the effect of grapefruit juice on intestinal absorption of talinolol between human and rat. J. Pharmacol. Exp. Ther., 332, 181–189 (2010).

    Article  PubMed  CAS  Google Scholar 

  • Westphal, K., Weinbrenner, A., Giessmann, T., Stuhr, M., Franke, G., Zschiesche, M., Oertel, R., Terhaag, B., Kroemer, H. K., and Siegmund, W., Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein. Clin. Pharmacol. Ther., 68, 6–12 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Yu, F., Takahashi, T., Moriya, J., Kawaura, K., Yamakawa, J., Kusaka, K., Itoh, T., Morimoto, S., Yamaguchi, N., and Kanda, T., Traditional Chinese medicine and Kampo: a review from the distant past for the future. J. Int. Med. Res., 34, 231–239 (2006).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kazunori Iwanaga.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Iwanaga, K., Arimune, K., Miyazaki, M. et al. Effects of furanocoumarins in Kampo extract-based medicines on rat intestinal absorption of CYP3A and P-glycoprotein substrate drugs in vivo . Arch. Pharm. Res. 35, 1055–1064 (2012). https://doi.org/10.1007/s12272-012-0613-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-012-0613-x

Key words

Navigation