Skip to main content

Advertisement

SpringerLink
Log in

Induction of cytochrome P450 2B6 activity by the herbal medicine baicalin as measured by bupropion hydroxylation

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This study investigated the effect of the herbal medicine baicalin on bupropion hydroxylation, a probe reaction for CYP2B6 activity related to different CYP2B6 genotype groups.

Method

Seventeen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6, and 5 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with baicalin. Blood samples were taken up to 72 h after each bupropion dose, and pharmacokinetics profiles were determined on days 1 and 25 for bupropion and hydroxybupropion.

Result

Baicalin administration increased hydroxybupropion maximum plasma concentration (C max) by 73% [90% confidence interval (CI), 44–108%; P < 0.01] and the area under the concentration time curve extrapolated to infinity (AUC0–∞) of hydroxybupropion by 87% (90% CI, 48–137%; P < 0.01), with no change in the elimination half-life of hydroxybupropion. Baicalin increased the AUC0–∞ ratio of hydroxybupropion to bupropion by 63% (90% CI, 38–92%; P < 0.01).

Conclusion

Baicalin significantly induced CYP2B6-catalyzed bupropion hydroxylation, and the effects of baicalin on other CYP2B6 substrate drugs deserve further investigation.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lu T (2007) Comparative pharmacokinetics of baicalin after oral administration of pure baicalin, Radix scutellariae extract and Huang-Lian-Jie-Du-Tang to rats. J Ethnopharmacol 110:412–418

    Article  PubMed  CAS  Google Scholar 

  2. Kawashima K, Fujimura Y, Makino T, Kano Y (2006) Pharmacological properties of traditional medicine (XXXII): protective effects of hangeshashinto and the combinations of its major constituents on gastric lesions in rats. Biol Pharm Bull 29:1973–1975

    Article  PubMed  CAS  Google Scholar 

  3. Li CY, Chiu CH, Huang HS, Lin CH, Wu TS (2006) High-performance liquid chromatographic method for simultaneous quantification of eight major biologically active ingredients in ‘Da-Chai-Hu-Tang’ preparation. Biomed Chromatogr 20:305–308

    Article  PubMed  Google Scholar 

  4. Lo YC et al (2005) San-Huang-Xie-Xin-Tang attenuates inflammatory responses in lipopolysaccharide-exposed rat lungs. J Ethnopharmacol 101:68–74

    Article  PubMed  CAS  Google Scholar 

  5. Liu CT, Wu CY, Weng YM, Tseng CY (2005) Ultrasound-assisted extraction methodology as a tool to improve the antioxidant properties of herbal drug Xiao-chia-hu-tang. J Ethnopharmacol 99:293–300

    Article  PubMed  Google Scholar 

  6. Zuo F et al (2003) Pharmacokinetic study on the multi-constituents of Huangqin-Tang decoction in rats. Biol Pharm Bull 26:911–919

    Article  PubMed  CAS  Google Scholar 

  7. Lininger SW, Gaby AR, Austin S, Brown DJ, Wright JV, Duncan A (2000) The natural pharmacy. Random House, New York

    Google Scholar 

  8. McGuffin M, Hobbs C, Upton R, Goldberg A (1997) American Herbal Products Association botanical safety handbook. CRC Press, Boca Raton

    Google Scholar 

  9. Hou YN, Zhu XY, Cheng GF (2000) Effects of baicalin on liver microsomal cytochrome P450 system. Acta Pharm Sin 35:890–892

    CAS  Google Scholar 

  10. Che QM, Huang XL, Li YM, Kun Z, Teruaki A, Masao H (2001) Studies on metabolites of baicalin in human urine (in Chinese). Zhongguo Zhong Yao Za Zhi 26(11):768–769

    PubMed  CAS  Google Scholar 

  11. Fan L et al (2008) The effect of herbal medicine baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-transporting polypeptide 1B1. Clin Pharmacol Ther 83:471–476

    Article  PubMed  CAS  Google Scholar 

  12. Ekins S et al (1998) Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther 286:1253–1259

    PubMed  CAS  Google Scholar 

  13. Gervot L et al (1999) Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9:295–306

    Article  PubMed  CAS  Google Scholar 

  14. Nolan D, Phillips E, Mallal S (2006) Efavirenz and CYP2B6 polymorphism: implications for drug toxicity and resistance. Clin Infect Dis 42:408–410

    Article  PubMed  CAS  Google Scholar 

  15. Faucette SR et al (2004) Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 32:348–358

    Article  PubMed  CAS  Google Scholar 

  16. Walsky RL, Astuccio AV, Obach RS (2006) Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol 46:1426–1438

    Article  PubMed  CAS  Google Scholar 

  17. Turpeinen M, Raunio H, Pelkonen O (2006) The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab 7:705–714

    Article  PubMed  CAS  Google Scholar 

  18. Kirchheiner J et al (2003) Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 13:619–626

    Article  PubMed  CAS  Google Scholar 

  19. Jacob RM, Johnstone EC, Neville MJ, Walton RT (2004) Identification of CYP2B6 sequence variants by use of multiplex PCR with allele-specific genotyping. Clin Chem 50:1372–1377

    Article  PubMed  CAS  Google Scholar 

  20. Zukunft J et al (2005) A natural CYP2B6 TATA box polymorphism (-82T→C) leading to enhanced transcription and relocation of the transcriptional start site. Mol Pharmacol 67:1772–1782

    Article  PubMed  CAS  Google Scholar 

  21. Klein K et al (2005) Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics 15:861–873

    Article  PubMed  CAS  Google Scholar 

  22. Guan S, Huang M, Chan E, Chen X, Duan W, Zhou SF (2006) Genetic polymorphisms of cytochrome P450 2B6 gene in Han Chinese. Eur J Pharm Sci 29:14–21

    Article  PubMed  CAS  Google Scholar 

  23. Cho JY et al (2004) Haplotype structure and allele frequencies of CYP2B6 in a Korean population. Drug Metab Dispos 32:1341–1344

    Article  PubMed  CAS  Google Scholar 

  24. Tsuchiya K et al (2004) Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 319:1322–1326

    Article  PubMed  CAS  Google Scholar 

  25. Lee AM et al (2007) CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biol Psychiatry 62:635–641

    Article  PubMed  CAS  Google Scholar 

  26. Hesse LM et al (2000) CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 28:1176–1183

    PubMed  CAS  Google Scholar 

  27. Faucette SR et al (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222–1230

    PubMed  CAS  Google Scholar 

  28. Faucette SR, Hawke RL, Shord SS, Lecluyse EL, Lindley CM (2001) Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation. Drug Metab Dispos 29:1123–1129

    PubMed  CAS  Google Scholar 

  29. Dunner DL et al (1998) A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry 59:366–373

    PubMed  CAS  Google Scholar 

  30. Johnston JA et al (2001) Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob Res 3:131–140

    Article  PubMed  CAS  Google Scholar 

  31. Bondarev ML, Bondareva TS, Young R, Glennon RA (2003) Behavioral and biochemical investigations of bupropion metabolites. Eur J Pharmacol 474:85–93

    Article  PubMed  CAS  Google Scholar 

  32. Damaj MI et al (2004) Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. Mol Pharmacol 66:675–682

    Article  PubMed  CAS  Google Scholar 

  33. Palovaara S, Pelkonen O, Uusitalo J, Lundgren S, Laine K (2003) Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation. Clin Pharmacol Ther 74:326–333

    Article  PubMed  CAS  Google Scholar 

  34. Turpeinen M et al (2005) Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther 77:553–559

    Article  PubMed  CAS  Google Scholar 

  35. Loboz KK et al (2006) Cytochrome P450 2B6 activity as measured by bupropion hydroxylation: effect of induction by rifampin and ethnicity. Clin Pharmacol Ther 80:75–84

    Article  PubMed  CAS  Google Scholar 

  36. Hogeland GW, Swindells S, McNabb JC, Kashuba AD, Yee GC, Lindley CM (2007) Lopinavir/ritonavir reduces bupropion plasma concentrations in healthy subjects. Clin Pharmacol Ther 81:69–75

    Article  PubMed  CAS  Google Scholar 

  37. Farid NA et al (2008) Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol 48:53–59

    Article  PubMed  CAS  Google Scholar 

  38. Hesse LM, Greenblatt DJ, Von Moltke LL, Court MH (2006) Ritonavir has minimal impact on the pharmacokinetic disposition of a single dose of bupropion administered to human volunteers. J Clin Pharmacol 46:567–576

    Article  PubMed  CAS  Google Scholar 

  39. Haynes KFS, Lindley C, LeCluyse E, Shord S, Hawke R (2002) Evaluation of buproprion hydroxylation as a probe for cytochrome P450 2B6 activity in cultured human hepatocytes. Poster. American College of Clinical Pharmacy Spring Practice and Research Forum, Savannah, GA, 10 April 2002

  40. Borges V, Yang E, Dunn J, Henion J (2004) High-throughput liquid chromatography-tandem mass spectrometry determination of bupropion and its metabolites in human, mouse and rat plasma using a monolithic column. J Chromatogr B Analyt Technol Biomed Life Sci 25:277–287

    Google Scholar 

  41. Hesse LM et al (2004) Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 14:225–238

    Article  PubMed  CAS  Google Scholar 

  42. Hesse LM, Sakai Y, Vishnuvardhan D, Li AP, Von Moltke LL, Greenblatt DJ (2003) Effect of bupropion on CYP2B6 and CYP3A4 catalytic activity, immunoreactive protein and mRNA levels in primary human hepatocytes: comparison with rifampicin. J Pharm Pharmacol 55:1229–1239

    Article  PubMed  CAS  Google Scholar 

  43. Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H, Pelkonen O (2004) Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos 32:626–631

    Article  PubMed  CAS  Google Scholar 

  44. Stewart JJ et al (2001) Single-dose pharmacokinetics of bupropion in adolescents: effects of smoking status and gender. J Clin Pharmacol 41:770–778

    Article  PubMed  CAS  Google Scholar 

  45. Lai MY, Hsiu SL, Tsai SY, Hou YC, Chao PD (2003) Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats. J Pharm Pharmacol 55(2):205–209

    Article  PubMed  CAS  Google Scholar 

  46. Taiming L, Xuehua J (2006) Investigation of the absorption mechanisms of baicalin and baicalein in rats. J Pharm Sci 95:1326–1333

    Article  PubMed  Google Scholar 

  47. Morris ME, Zhang S (2006) Flavonoid-drug interactions: effects of flavonoids on ABC transporters. Life Sci 78:2116–2130

    Article  PubMed  CAS  Google Scholar 

  48. Moon YJ, Wang X, Morris ME (2006) Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro 20:187–210

    Article  PubMed  CAS  Google Scholar 

  49. Hong SS, Seo K, Lim SC, Han HK (2007) Interaction characteristics of flavonoids with human organic anion transporter 1 (hOAT1) and 3 (hOAT3). Pharmacol Res 56:468–473

    Article  PubMed  CAS  Google Scholar 

  50. Ekins S, Wrighton SA (1999) The role of CYP2B6 in human xenobiotic metabolism. Drug Metab Rev 31:719–754

    Article  PubMed  CAS  Google Scholar 

  51. Sridar C, Kent UM, Notley LM, Gillam EM, Hollenberg PF (2002) Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6. J Pharmacol Exp Ther 301:945–952

    Article  PubMed  CAS  Google Scholar 

  52. Kharasch ED, Hoffer C, Whittington D, Sheffels P (2004) Role of hepatic and intestinal cytochrome CYP3A and CYP2B6 in the metabolism, disposition and miotic effects of methadone. Clin Pharmacol Ther 76:250–269

    Article  PubMed  CAS  Google Scholar 

  53. Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED (2007) Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther 321:389–399

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China 30528026, 30300428, 30672497, 30500623, and 30572225, by the China Medical Board of New York grant 01-755, and the Hunan Health Research Foundation of Traditional Chinese Medicine grant 204041.

Conflict of interest

None of the authors has any conflict of interest regarding this study.

Author information

Authors and Affiliations

  1. Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, 410078, People’s Republic of China

    Lan Fan, Jin-Chao Wang, Zhi-Rong Tan, Yao Chen, Qing Li, Wei Zhang, Guo Wang, He-Ping Lei, Dong-Li Hu, Dan Wang & Hong-Hao Zhou

  2. Department of Clinical Pharmacology, Inje University, Pusan, Korea

    Feng Jiang

Authors
  1. Lan Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Chao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhi-Rong Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. He-Ping Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dong-Li Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hong-Hao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-Hao Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fan, L., Wang, JC., Jiang, F. et al. Induction of cytochrome P450 2B6 activity by the herbal medicine baicalin as measured by bupropion hydroxylation. Eur J Clin Pharmacol 65, 403–409 (2009). https://doi.org/10.1007/s00228-008-0594-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-008-0594-3

Keywords

Search

Navigation