Archives of Pharmacal Research

, Volume 33, Issue 12, pp 2025–2031 | Cite as

Absence of drug interaction between Hwang-Ryun-Hae-Dok-Tang and Phenolsulfonphthalein

  • Hong Jae Yi
  • Ju-Hee Oh
  • Young-Joo LeeEmail author
Research Articles Drug Actions


Hwang-Ryun-Hae-Dok-Tang (HT; a standardized herbal formula consisting of extracts from Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus) was reported to modulate a function of multidrug resistance associated protein 2 (Mrp2) in vitro. The aim of this study was to assess the in vivo pharmacokinetic interactions between HT and phenolsulfonphthalein (PSP), a typical model Mrp2 substrate eliminated via bile through Mrp2 in rats. Rats received intravenous PSP (0.8 mg/kg) followed by either a single oral dose of HT (0.42 g/kg) or multiple oral doses of HT (0.42 g/kg for 7 days). The effect of HT treatment was also investigated at a steady-state after intravenous PSP infusion. In contrast to previous in vitro results, in this study, we found that the HT-treated and control groups did not show any significant difference in the plasma PSP concentration and pharmacokinetic parameters, including area under the plasma concentration-time curve (AUC; control: 118 ± 19, single dose: 116 ± 40, and multiple dose: 137 ± 4, in mg/(min·mL)) and biliary clearance (control: 3.15 ± 0.69, single dose: 2.59 ± 1.11, and multiple dose: 2.53 ± 0.65, in mL/(min·kg)). However, cyclosporine A (5 mg/kg, an inhibitor of Mrp2) significantly decreased the AUC and biliary clearance of PSP. The steady-state plasma concentration and biliary clearance of PSP-were also similar between the groups. Taken together, our results suggest that HT may not be affected by Mrp2-mediated herb-drug interaction in vivo.

Key words

Herb-drug interaction Pharmacokinetics Hwang-Ryun-Hae-Dok-Tang Phenolsulfonphthalein Biliary excretion 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akao, T., Hanada, M., Sakashita, Y., Sato, K., Morita, M., and Imanaka, T., Efflux of baicalin, a flavone glucuronide of Scutellariae Radix, on Caco-2 cells through multidrug resistance-associated protein 2. J. Pharm. Pharmacol., 59, 87–93 (2007).CrossRefPubMedGoogle Scholar
  2. Alvarez, A. I., Real, R., Pérez, M., Mendoza, G., Prieto, J. G., and Merino, G., Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response. J. Pharm. Sci., 99, 598–617 (2010).PubMedGoogle Scholar
  3. Arakawa, K., Saruta, T., Abe, K., Iimura, O., Ishii, M., Ogihara, T., Hiwada, K., Fukiyama, K., Fujishima, M., Mizuno, Y., Kikuchi, T., and Takaori, S., Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study. Phytomedicine, 13, 1–10 (2006).CrossRefPubMedGoogle Scholar
  4. Boesch, D., Gavériaux, C., Jachez, B., Pourtier-Manzanedo, A., Bollinger, P., and Loor, F., In vivo circumvention of Pglycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res., 51, 4226–4233 (1991).PubMedGoogle Scholar
  5. Böhme, M., Müller, M., Leier, I., Jedlitschky, G., and Keppler, D., Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in rat liver. Gastroenterology, 107, 255–265 (1994).PubMedGoogle Scholar
  6. Ernst, E. and Pittler, M. H., Risks associated with herbal medicinal products. Wien. Med. Wochenschr., 152, 183–189 (2002).CrossRefPubMedGoogle Scholar
  7. Gerk, P. M. and Vore, M., Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J. Pharmacol. Exp. Ther., 302, 407–415 (2002).CrossRefPubMedGoogle Scholar
  8. Gibaldi, M. and Perrier, D., Pharmacokinetics, Marcel-Dekker, New York, (1982).Google Scholar
  9. Gupta, D., Jalali, M., Wells, A., and Dasgupta, A., Drug-herb interactions: unexpected suppression of free Danshen concentrations by salicylate. J. Clin. Lab. Anal., 16, 290–294 (2002).CrossRefPubMedGoogle Scholar
  10. Hennessy, M., Kelleher, D., Spiers, J. P., Barry, M., Kavanagh, P., Back, D., Mulcahy, F., and Feely, J., St Johns wort increases expression of P-glycoprotein: implications for drug interactions. Br. J. Clin. Pharmacol., 53, 75–82 (2002).CrossRefPubMedGoogle Scholar
  11. Herédi-Szabó, K., Jemnitz, K., Kis, E., Ioja, E., Jánossy, J., Vereczkey, L., and Krajcsi, P., Potentiation of MRP2/Mrp2-mediated estradiol-17beta-glucuronide transport by drugs-a concise review. Chem. Biodivers., 6, 1970–1974 (2009).CrossRefPubMedGoogle Scholar
  12. Huang, R., Murry, D. J., Kolwankar, D., Hall, S. D., and Foster, D. R., Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines. Biochem. Pharmacol., 71, 1695–1704 (2006).CrossRefPubMedGoogle Scholar
  13. Hwang, Y. S., Shin, C. Y., Huh, Y., and Ryu, J. H., Hwangryun-Hae-Dok-tang (Huanglian-Jie-Du-Tang) extract and its constituents reduce ischemia-reperfusion brain injury and neutrophil infiltration in rats. Life Sci., 71, 2105–2117 (2002).CrossRefPubMedGoogle Scholar
  14. Itagaki, S., Sugawara, M., Kobayashi, M., Miyazaki, K., and Iseki, K., Mechanism of active secretion of phenolsulfon-phthalein in the liver via Mrp2 (abcc2), an organic anion transporter. Drug Metab. Pharmacokinet., 18, 238–244 (2003).CrossRefPubMedGoogle Scholar
  15. Li, X. Z., Lei, P., and Liu, S., Determination of 3 kinds of components in huanglian jiedu decoction by HPLC under different UV wavelengths. Zhongguo Zhong Yao Za Zhi, 31, 1686–1688 (2006).PubMedGoogle Scholar
  16. Mizukawa, H., Yoshida, K., Honmura, A., Uchiyama, Y., Kaku, H., Nakajima, S., and Haruki, E., The effect of orengedokuto on experimentally-inflamed rats. Am. J. Chin. Med., 21, 71–78 (1993).CrossRefPubMedGoogle Scholar
  17. Moore, L. B., Goodwin, B., Jones, S. A., Wisely, G. B., Serabjit-Singh, C. J., Willson, T. M., Collins, J. L., and Kliewer, S. A., St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad. Sci. U.S.A., 97, 7500–7502 (2000).CrossRefPubMedGoogle Scholar
  18. Shoda, J., Miura, T., Utsunomiya, H., Oda, K., Yamamoto, M., Kano, M., Ikegami, T., Tanaka, N., Akita, H., Ito, K., Suzuki, H., and Sugiyama, Y., Genipin enhances Mrp2 (Abcc2)-mediated bile formation and organic anion transport in rat liver. Hepatology, 39, 167–178 (2004).CrossRefPubMedGoogle Scholar
  19. Suenaga, T., Shirakawa, T., Harada, N., Tao, C., Yamasaki, M., Komatsu, H., Matsumoto, N., Kida, M., Kawamoto, Y., Murakami, Y. et al., Mechanism of protective effects of ouren-gedoku-to and san’ou-syashin-to on the gastric mucosa. Nippon Yakurigaku Zasshi, 98, 319–325 (1991).CrossRefPubMedGoogle Scholar
  20. Yamasaki, K., Kajimura, K., Nakano, M., Yokoyama, H., Yoneda, K., and Umezawa, C., Effects of preparations of Chinese medicinal prescriptions on digestive enzymes in vitro and in vivo. Biol. Pharm. Bull., 21, 133–139 (1998).PubMedGoogle Scholar
  21. Yang, C. S., Sang, S., Lambert, J. D., and Lee, M. J., Bioavailability issues in studying the health effects of plant polyphenolic compounds. Mol. Nutr. Food Res., 52Suppl 1, S139–S151 (2008).PubMedGoogle Scholar
  22. Zakeri-Milani, P., Barzegar-Jalali, M., Tajerzadeh, H., Azarmi, Y., and Valizadeh, H., Simultaneous determination of naproxen, ketoprofen and phenol red in samples from rat intestinal permeability studies: HPLC method development and validation. J. Pharm. Biomed. Anal., 39, 624–630 (2005).CrossRefPubMedGoogle Scholar
  23. Zhang, D. M., He, Z. W., Liu, X. D., Li, Y., Xie, L., Wang, G.J., and Liu, L., In-vivo and in-vitro studies on the effect of Huang-Lian-Jie-Du-Tang on nimodipine transport across rat blood-brain barrier. J. Pharm. Pharmacol., 59, 1733–1738 (2007).CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2010

Authors and Affiliations

  1. 1.College of PharmacyKyung Hee UniversitySeoulKorea
  2. 2.Department of Life and Nanopharmaceutical SciencesKyung Hee UniversitySeoulKorea
  3. 3.Division of Biopharmaceutics, College of PharmacyKyung Hee UniversitySeoulKorea

Personalised recommendations