Archives of Pharmacal Research

, Volume 36, Issue 1, pp 1–5 | Cite as

Evaluation of DA-9801, a new herbal drug for diabetic neuropathy, on metabolism-mediated interaction

  • Hye Young Ji
  • Kwang Hyeon Liu
  • Tae Yeon Kong
  • Hyeon-Uk Jeong
  • Sang-Zin Choi
  • Miwon Son
  • Yong-Yeon Cho
  • Hye Suk Lee
Report on Investigational Drugs

Abstract

DA-9801, the mixture extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new herbal drug currently being evaluated in a phase II clinical study for the treatment of diabetic peripheral neuropathy in Korea. The inhibitory potentials of DA-9801, D. rhizoma extract, D. nipponica Makino extract, and dioscin, an active component of DA-9801, on eight human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes were investigated in human liver microsomes using liquid chromatography–tandem mass spectrometry. DA-9801 showed slight inhibition of CYP1A2, CYP2C8, UGT1A1, and UGT1A9 enzyme activities with IC50 values of 396.4, 449.9, 226.0, and 408.8 μg/mL, respectively. D. rhizoma extract showed negligible inhibition of CYP and UGT activities, but D. nipponica extract slightly inhibited CYP1A2, CYP2C8, CYP2C9, UGT1A1, and UGT1A9 activities with IC50 values of 264.2, 237.1, 206.8, 302.4, and 383.1 μg/mL, respectively. DA-9801 showed volume per dose index values of 0.44–0.88 L for a 200-mg dose, suggesting that they may not cause the inhibition of the metabolism of CYP1A2, CYP2C8, UGT1A1, and UGT1A9-catalyzed drugs in humans. These results suggest that the administration of DA-9801 in human may not cause clinically relevant inhibition of these enzymes.

Keywords

DA-9801 Cytochrome P450 UDP-glucuronosyltransferase Human liver microsomes Drug–drug interaction 

References

  1. Apfel, S.C., S. Schwartz, B.T. Adornato, R. Freeman, V. Biton, M. Rendell, A. Vinik, M. Giuliani, J.C. Stevens, R. Barbano, and P.J. Dyck. 2000. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group. The Journal of the American Medical Association 284: 2215–2221.CrossRefGoogle Scholar
  2. Argoff, C.E., B.E. Cole, D.A. Fishbain, and G.A. Irving. 2006. Diabetic peripheral neuropathic pain: Clinical and quality-of-life issues. Mayo Clinic Proceedings 81(4 Suppl): S3–11.PubMedCrossRefGoogle Scholar
  3. Borrelli, F., and A.A. Izzo. 2009. Herb-drug interactions with St. John’s wort (Hypericum perforatum): an update on clinical observations. American Association of Pharmaceutical Scientists Journal 11: 710–727.PubMedGoogle Scholar
  4. Calcutt, N.A., D.R. Tomlinson, G.B. Willars, and P. Keen. 1990. Axonal transport of substance P-like immunoreactivity in ganglioside-treated diabetic rats. Journal of the Neurological Sciences 96: 283–291.PubMedCrossRefGoogle Scholar
  5. Chen, X.W., E.S. Serag, K.B. Sneed, J. Liang, H. Chew, S.Y. Pan, and S.F. Zhou. 2011. Clinical herbal interactions with conventional drugs: From molecules to maladies. Current Medicinal Chemistry 18: 4836–4850.PubMedCrossRefGoogle Scholar
  6. Choi, S.Z., and M. Son. 2011. Novel botanical drug for the treatment of diabetic neuropathy. Archives of Pharmacal Research 34: 865–867.PubMedCrossRefGoogle Scholar
  7. Choi, S., H. Kim, J. Ryu, Y. Cho, M. Son, and S.Y. Kim. 2011a. A novel botanical drug (DA-9801) for the treatment of diabetic neuropathy. Planta Medica 77: PL17.Google Scholar
  8. Choi, Y.H., Y.W. Chin, and Y.G. Kim. 2011b. Herb–drug interactions: focus on metabolic enzymes and transporters. Archives of Pharmacal Research 34: 1843–1863.PubMedCrossRefGoogle Scholar
  9. He, S.M., E. Chan, and S.F. Zhou. 2010a. ADME properties of herbal medicines in humans: evidence, challenges and strategies. Current Pharmaceutical Design 17: 357–407.CrossRefGoogle Scholar
  10. He, S.M., A.K. Yang, X.T. Li, Y.M. Du, and S.F. Zhou. 2010b. Effects of herbal products on the metabolism and transport of anticancer agents. Expert Opinion on Drug Metabolism and Toxicology 6: 1195–1213.PubMedCrossRefGoogle Scholar
  11. Hikino, H., C. Konno, M. Takahashi, M. Murakami, Y. Kato, M. Karikura, and T. Hayashi. 1986. Isolation and hypoglycemic activity of dioscorans A, B, C, D, E, and F; glycans of Dioscorea japonica rhizophors. Planta Medica 52: 168–171.CrossRefGoogle Scholar
  12. Hu, K., and X. Yao. 2003. The cytotoxicity of methyl protodioscin against human cancer cell lines in vitro. Cancer Investigation 21: 389–393.PubMedCrossRefGoogle Scholar
  13. Ji, H.Y., K.H. Liu, H. Lee, S.R. Im, H.J. Shim, M. Son, and H.S. Lee. 2011. Corydaline inhibits multiple cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes. Molecules 16: 6591–6602.PubMedCrossRefGoogle Scholar
  14. Ji, H.Y., K.H. Liu, J.H. Jeong, D.Y. Lee, H.J. Shim, M. Son, and H.S. Lee. 2012. Effect of a new prokinetic agent DA-9701 formulated with Corydalis Tuber and Pharbitidis Semen on cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes. Evidence-Based Complementary and Alternative Medicine: eCAM 2012: 650718.PubMedCrossRefGoogle Scholar
  15. Kang, T.H., S.Z. Choi, T.H. Lee, M.W. Son, and S.Y. Kim. 2008a. Characteristics of antidiabetic effect of Dioscorea rhizome (1)—hypoglycemic effect. Korean Journal of Food and Nutrition 21: 425–429.Google Scholar
  16. Kang, T.H., S.Z. Choi, T.H. Lee, M.W. Son, J.H. Park, and S.Y. Kim. 2008b. Characteristics of antidiabetic effect of Dioscorea rhizome (2)—Prevention of diabetic neuropathy by NGF induction. Korean Journal of Food and Nutrition 21: 430–435.Google Scholar
  17. Kang, T.H., E. Moon, B.N. Hong, S.Z. Choi, M. Son, J.H. Park, and S.Y. Kim. 2011. Diosgenin from Dioscorea nipponica ameliorates diabetic neuropathy by inducing nerve growth factor. Biological and Pharmaceutical Bulletin 34: 1493–1498.PubMedCrossRefGoogle Scholar
  18. Kim, M.W. 1998. Effect of H2O fraction of Dioscorea japonica thunb with Selenium on plasma glucose and lipid metabolism in streptozotocin induced diabetic rats. Korean Journal of Nutrition 31: 1377–1384.Google Scholar
  19. Kim, M.J., H.N. Kim, K.S. Kang, N.I. Baek, D.K. Kim, Y.S. Kim, S.H. Kim, and B.H. Jean. 2004. Methanol extract of Dioscoreae rhizoma inhibits pro-inflammatory cytokines and mediators in the synoviocytes of rheumatoid arthritis. International Immunopharmacology 4: 1489–1497.PubMedCrossRefGoogle Scholar
  20. Kim, K.H., M.A. Kim, E. Moon, S.Y. Kim, S.Z. Choi, M. Son, and K.R. Lee. 2011a. Furostanol saponins from the rhizomes of Dioscorea japonica and their effects on NGF induction. Bioorganic & Medicinal Chemistry Letters 21: 2075–2078.CrossRefGoogle Scholar
  21. Kim, N., S.H. Kim, Y.J. Kim, J.K. Kim, M.K. Nam, H. Rhim, S.K. Yoon, S.Z. Choi, M. Son, S.Y. Kim, and H.J. Kuh. 2011b. Neurotrophic activity of DA-9801, a mixture extract of Dioscorea japonica Thunb. and Dioscorea nipponica Makino, in vitro. Journal of Ethnopharmacology 137: 312–319.PubMedCrossRefGoogle Scholar
  22. Kim, D.H., B.N. Hong, H.T. Lee, H.N. Hong, C.W. Lim, K.H. Park, T.W. Kim, and T.H. Kang. 2012. Small molecular weight PEGylation of diosgenin in an in vivo animal study for diabetic auditory impairment treatment. Bioorganic & Medicinal Chemistry Letters 22: 4609–4612.CrossRefGoogle Scholar
  23. Levi-Montalcini, R. 1987. The nerve growth factor 35 years later. Science 237: 1154–1162.PubMedCrossRefGoogle Scholar
  24. Li, H., W. Huang, Y. Wen, G. Gong, Q. Zhao, and G. Yu. 2010. Anti-thrombotic activity and chemical characterization of steroidal saponins from Dioscorea zingiberensis C.H. Wright. Fitoterapia 81: 1147–1156.PubMedCrossRefGoogle Scholar
  25. Mohamed, M.E., and R.F. Frye. 2011. Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Medica 77: 311–321.PubMedCrossRefGoogle Scholar
  26. Na, D.H., H.Y. Ji, E.J. Park, K.H. Liu, and H.S. Lee. 2011. In vitro assessment of metabolism-mediated herb–drug interactions. Archives of Pharmacal Reseach 34: 259–263.Google Scholar
  27. Scheen, A.J. 2010. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes, Obesity & Metabolism 12: 648–658.CrossRefGoogle Scholar
  28. Strandell, J., A. Neil, and G. Carlin. 2004. An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies. Phytomedicine 11: 98–104.PubMedCrossRefGoogle Scholar
  29. Vinik, A.I., T.S. Park, K.B. Stansberry, and G.L. Pittenger. 2000. Diabetic neuropathies. Diabetologia 43: 957–973.PubMedCrossRefGoogle Scholar
  30. Vinik, A.I., B.D. Mitchell, R.E. Maser, and R. Freeman. 2003. Diabetic autonomic neuropathy. Diabetes Care 26: 1553–1579.PubMedCrossRefGoogle Scholar
  31. Wu, J.W., L.C. Lin, and T.H. Tsai. 2009. Drug–drug interactions of silymarin on the perspective of pharmacokinetics. Journal of Ethnopharmacology 121: 185–193.PubMedCrossRefGoogle Scholar
  32. Yin, J., Y. Tezuka, K. Kouda, Q.L. Tran, T. Miyahara, Y. Chen, and S. Kadota. 2004. Antiosteoporotic activity of the water extract of Dioscorea spongiosa. Biological and Pharmaceutical Bulletin 27: 583–586.PubMedCrossRefGoogle Scholar
  33. Zhou, S.F., Z.W. Zhou, C.G. Li, X. Chen, X. Yu, C.C. Xue, and A. Herington. 2007. Identification of drugs that interact with herbs in drug development. Drug Discovery Today 12: 664–673.PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Hye Young Ji
    • 1
  • Kwang Hyeon Liu
    • 2
  • Tae Yeon Kong
    • 1
  • Hyeon-Uk Jeong
    • 1
  • Sang-Zin Choi
    • 3
  • Miwon Son
    • 3
  • Yong-Yeon Cho
    • 1
  • Hye Suk Lee
    • 1
    • 4
  1. 1.College of Pharmacy and Integrated Research Institute of Pharmaceutical SciencesThe Catholic University of KoreaBucheonKorea
  2. 2.College of Pharmacy and Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguKorea
  3. 3.Research CenterDong-A Pharmaceutical Co.YonginKorea
  4. 4.Drug Metabolism & Bioanalysis Lab., College of PharmacyThe Catholic University of KoreaBucheonKorea

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