Planta Med 2010; 76(3): 245-250
DOI: 10.1055/s-0029-1186082
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Herb-Drug Interactions: In Vivo and In Vitro Effect of Shenmai Injection, a Herbal Preparation, on the Metabolic Activities of Hepatic Cytochrome P450 3A1/2, 2C6, 1A2, and 2E1 in Rats

Chun-hua Xia1 , 2 [*] , Jian-guo Sun1 [*] , Guang-ji Wang1 , Li-li Shang1 , Xiao-xuan Zhang1 , Rong Zhang1 , Ying Peng1 , Xiao-jin Wang1 , Hai-ping Hao1 , Lin Xie1 , Michael S. Roberts3
  • 1Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
  • 2Clinical Pharmacology Institute, Medical College of Nanchang University, Nanchang, China
  • 3Therapeutics Research Unit, Southern Clinical Division, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia
Further Information

Publication History

received February 24, 2009 revised July 29, 2009

accepted August 3, 2009

Publication Date:
11 September 2009 (online)

Abstract

Shenmai injection (SMI), a mixture of Radix Ginseng and Radix Ophiopogonis, is one of the most popular herbal medicinal products and is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of SMI, in vivo and in vitro, on the metabolic activities of hepatic cytochrome CYP450 3A1/2, 2C6, 2E1, and 1A2 in rats. After a single or multiple pretreatment with SMI, the rats were administrated intravenously a cocktail containing midazolam (1 mg/kg), diclofenac (0.5 mg/kg), theophylline (1 mg/kg), and chlorzoxazone (0.5 mg/kg) as probe substrates of rat CYP450 3A1/2, 2C6, 1A2, and 2E1, respectively. Single and multiple SMI pretreatment to rats resulted in a rise of 33.8 % (p < 0.01) and 25.6 % (p < 0.01) in AUC for midazolam, and an increase in AUC for diclofenac by 14.7 % (p < 0.05) and 31.2 % (p < 0.01), respectively. However, the pharmacokinetics of chlorzoxazone and theophylline in rats was not altered markedly. In rat liver microsomes, linear mixed-type inhibition of SMI against the enzyme activities of CYP3A1/2, CYP2C6, and CYP1A2 was shown with IC50 values of 3.3 %, 2.0 %, and 3.1 % and K i values of 3.8 %, 1.5 %. and 1.9 %, respectively. These in vivo and in vitro results demonstrated that SMI had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats.

References

  • 1 Astin J A. Why patients use alternative medicine: results of a national study.  JAMA. 1998;  279 1548-1553
  • 2 Yang P. Chinese traditional medicine. The status in USA and FDA regulation.  J Chin Pharm Univ. 2007;  27 385-390
  • 3 Zhou S, Chan E, Pan S Q, Huang M, Lee E J. Pharmacokinetic interactions of drugs with St. John's wort.  J Psychopharmacol. 2004;  18 262-276
  • 4 Piscitelli S C, Burstein A H, Welden N, Gallicano K D, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir.  Clin Infect Dis. 2002;  34 234-238
  • 5 Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers.  Br J Clin Pharmacol. 2003;  55 199-202
  • 6 Fuhr U. Drug interactions with grapefruit juice: extent, probable mechanism and clinical relevance.  Drug Saf. 1998;  18 251-272
  • 7 Janetzky K, Morreale A P. Probable interaction between warfarin and ginseng.  Am J Health Syst Pharm. 1997;  54 692-693
  • 8 Yuan C S, Wei G, Dey L, Karrison T. American ginseng reduces warfarin's effect in healthy patients: a randomized controlled trial.  Ann Intern Med. 2004;  141 23-27
  • 9 Jiang X, Williams K M, Liauw W S, Ammit A J, Roufogalis B D, Duke C C, Day R O, McLachlan A J. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.  Br J Clin Pharmacol. 2004;  57 592-599
  • 10 Donovan J L, DeVane C L, Chavin K D, Taylor R M, Markowitz J S. Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers.  Drug Metab Dispos. 2003;  31 519-522
  • 11 Gurley B J, Gardner S F, Hubbard M A, Williams D K, Gentry W B, Cui Y, Ang C Y. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.  Clin Pharmacol Ther. 2002;  72 276-287
  • 12 Coon J T, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions.  Drug Saf. 2002;  25 323-344
  • 13 Floby E, Briem S, Terelius Y, Sohlenius-Sternbeck A K. Use of a cocktail of probe substrates for drug-metabolizing enzymes for the assessment of the metabolic capacity of hepatocyte preparations.  Xenobiotica. 2004;  34 949-959
  • 14 Shelepova T, Nafziger A N, Victory J, Kashuba A D, Rowland E, Zhang Y, Sellers E, Kearns G, Leeder J S, Gaedigk A, Bertino J S. Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5 + 1 cocktail.  J Clin Pharmacol. 2005;  45 1413-1421
  • 15 Krösser S, Neugebauer R, Dolgos H, Fluck M, Rost K L, Kovar A. Investigation of sarizotan's impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial.  Eur J Clin Pharmacol. 2006;  62 277-284
  • 16 Ryu J Y, Song I S, Sunwoo Y E, Shon J H, Liu K H, Cha I J, Shin J G. Development of the Inje “cocktail” for high-throughput evaluation of five human cytochrome P450 isoforms in vivo.  Clin Pharmacol Ther. 2007;  82 531-540
  • 17 Tang H, Min G T, Ge B, Li Y M, Liu X, Jiang S X. Evaluation of protective effects of Chi-Zhi-Huang decoction on phase I drug metabolism of liver injured rats by cocktail probe drugs.  J Ethnopharmacol. 2008;  117 420-426
  • 18 Rogers J F, Rocci M L, Haughey D B, Bertino J S. An evaluation of the suitability of intravenous midazolam as an in vivo marker for hepatic cytochrome P4503A activity.  Clin Pharmacol Ther. 2003;  73 153-158
  • 19 Yasui-Furukori N, Inoue Y, Tateishi T. Sensitive determination of midazolam and 1-hydroxymidazolam in plasma by liquid–liquid extraction and column-switching liquid chromatography with ultraviolet absorbance detection and its application for measuring CYP3A activity.  J Chromatogr B Analyt Technol Biomed Life Sci. 2004;  811 153-157
  • 20 Kobayashi K, Urashima K, Shimada N, Chiba K. Substrate specificity for rat cytochrome P450 (CYP) isoforms: screening with cDNA-expressed systems of the rat.  Biochem Pharmacol. 2002;  63 889-896
  • 21 Bruyère A, Declevès X, Bouzom F, Proust L, Martinet M, Walther B, Parmentier Y. Development of an optimized procedure for the preparation of rat intestinal microsomes: comparison of hepatic and intestinal microsomal cytochrome P450 enzyme activities in two rat strains.  Xenobiotica. 2009;  39 22-32
  • 22 Tang W, Stearns R A, Wang R W, Chiu S H, Baillie T A. Roles of human hepatic cytochrome P450 s 2C9 and 3A4 in the metabolic activation of diclofenac.  Chem Res Toxicol. 1999;  12 192-199
  • 23 Bachmann K, Sanyal G, Potter J, Schiavone R, Loch J. In vivo evidence that theophylline is metabolized principally by CYP1A in rats.  Pharmacology. 1993;  47 1-7
  • 24 Gu L, Gonzalez F J, Kalow W, Tang B K. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA expressed human CYP1A2 and CYP2E1.  Pharmacogenetics. 1992;  2 73-77
  • 25 Rockich K, Blouin R. Effect of the acute-phase response on the pharmacokinetics of chlorzoxazone and cytochrome P-450 2E1 in vitro activity in rats.  Drug Metab Dispos. 1999;  27 1074-1077
  • 26 Ahn C Y, Bae S K, Jung Y S, Lee I, Kim Y C, Lee M G, Shin W G. Pharmacokinetic parameters of chlorzoxazone and its main metabolite, 6-hydroxychlorzoxazone, after intravenous and oral administration of chlorzoxazone to liver cirrhotic rats with diabetes mellitus.  Drug Metab Dispos. 2008;  36 1233-1241
  • 27 Zhu M, Chan K W, Ng L S, Chang Q, Chang S, Li R C. Possible influences of ginseng on the pharmacokinetics and pharmacodynamics of warfarin in rats.  J Pharm Pharmacol. 1999;  51 175-180
  • 28 Lee S H, Ahn Y M, Ahn S Y, Doo H K, Lee B C. Interaction between warfarin and Panax ginseng in ischemic stroke patients.  J Altern Complement Med. 2008;  14 715-721
  • 29 Henderson G L, Harkey M R, Gershwin M E, Hackman R M, Stern J S, Stresser D M. Effects of ginseng components on cDNA-expressed cytochrome P450 enzyme catalytic activity.  Life Sci. 1999;  65 209-214
  • 30 Liu Y, Ma H, Zhang J W, Deng M C, Yang L. Influence of ginsenoside Rh1 and F1 on human cytochrome p 450 enzymes.  Planta Med. 2006;  72 126-131

1 These authors contributed equally to this work.

Prof. Guangji Wang

Key Lab of Drug Metabolism and Pharmacokinetics
China Pharmaceutical University

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210009 Nanjing

P. R. China

Phone: + 86 25 83 27 11 28

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Email: guangjiwang@hotmail.com