Skip to main content

Advertisement

SpringerLink
Log in

Artemisinin and CYP2A6 activity in healthy subjects

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

Abstract

Objective

To investigate whether the antimalarial drug artemisinin affects CYP2A6 activity in healthy subjects and to compare the utility of coumarin and nicotine as in vivo probe compounds for CYP2A6.

Methods

Twelve healthy male Vietnamese subjects were given coumarin or nicotine in randomized sequence before and after 5 days of a repeated oral administration of artemisinin during two different treatment periods 1 month apart. Sequential blood samples were drawn at baseline 7 days prior to artemisinin treatment and on the first and fifth day of artemisinin treatment during both treatment periods. Plasma concentrations of 7-hydroxycoumarin glucuronide (7-OHCG), nicotine, cotinine and artemisinin were analysed by high-performance liquid chromatography and those of coumarin and 7-hydroxycoumarin (7-OHC) were determined by liquid chromatography-tandem mass spectrometry. Urine, collected in two time intervals on the days of coumarin intake, was treated with β-glucuronidase and analysed for 7-OHC levels.

Results

Artemisinin \( AUC_{{0 - \infty }} \) values decreased significantly to 23% [95% confidence interval (CI) 18%–28%] on the fifth day of artemisinin administration as compared with the first. The sum of renally excreted 7-OHC and 7-OHCG increased by 1.55-fold (adjusted 95% CI 1.08–2.23) in the 3- to 8-h interval compared to baseline 7 days before. The 7-OHCG/7-OHC plasma \( AUC_{{0 - \infty }} \) ratio increased by 1.72-fold (adjusted 95% CI 1.16–2.54) following 5 days of artemisinin intake. There was no significant change in the cotinine/nicotine AUC0–11 hr ratio between study days.

Conclusion

Artemisinin significantly increased the sum of renally excreted 7-OHC and 7-OHCG in one of the two collection intervals, suggesting an induction of CYP2A6. A significant increase in the 7-OHCG to 7-OHC \( AUC_{{0 - \infty }} \) ratio indicates artemisinin to be an inducer of glucuronidation.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Ashton M, Hai TN, Sy ND, Huong DX, Van Huong N, Nieu NT, Cong LD (1998) Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults. Drug Metab Dispos 26(1):25–27

    PubMed  CAS  Google Scholar 

  2. Ashton M, Nguyen DS, Nguyen VH, Gordi T, Trinh NH, Dinh XH, Nguyen TN, Le DC (1998) Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria. Clin Pharmacol Ther 63(4):482–493

    Article  PubMed  CAS  Google Scholar 

  3. Asimus S, Gordi T (2007) Retrospective analysis of artemisinin pharmacokinetics: application of a semiphysiological autoinduction model. Br J Clin Pharmacol 63(6):758–762

    Article  PubMed  CAS  Google Scholar 

  4. Asimus S, Elsherbiny D, Hai TN, Jansson B, Huong NV, Petzold MG, Simonsson US, Ashton M (2007) Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects. Fundam Clin Pharmacol 21(3):307–416

    Article  PubMed  CAS  Google Scholar 

  5. Bapiro TE, Egnell AC, Hasler JA, Masimirembwa CM (2001) Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos 29(1):30–35

    PubMed  CAS  Google Scholar 

  6. Bapiro TE, Sayi J, Hasler JA, Jande M, Rimoy G, Masselle A, Masimirembwa CM (2005) Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans. Eur J Clin Pharmacol 61(10):755–761

    Article  PubMed  CAS  Google Scholar 

  7. Bogan DP, O’Kennedy R (1996) Simultaneous determination of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in human serum and plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 686(2):267–273

    Article  PubMed  CAS  Google Scholar 

  8. Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, Avery MA, Fromm MF, Eichelbaum M (2005) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 67(6):1954–1965

    Article  PubMed  CAS  Google Scholar 

  9. Cashman JR, Park SB, Yang ZC, Wrighton SA, Jacob P, 3rd, Benowitz NL (1992) Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N′-oxide. Chem Res Toxicol 5(5):639–646

    Article  PubMed  CAS  Google Scholar 

  10. Chen Y, Ferguson SS, Negishi M, Goldstein JA (2003) Identification of constitutive androstane receptor and glucocorticoid receptor binding sites in the CYP2C19 promoter. Mol Pharmacol 64(2):316–324

    Article  PubMed  CAS  Google Scholar 

  11. Cholerton S, Idle ME, Vas A, Gonzalez FJ, Idle JR (1992) Comparison of a novel thin-layer chromatographic-fluorescence detection method with a spectrofluorometric method for the determination of 7-hydroxycoumarin in human urine. J Chromatogr 575(2):325–330

    Article  PubMed  CAS  Google Scholar 

  12. Cohen AJ (1979) Critical review of the toxicology of coumarin with special reference to interspecies differences in metabolism and hepatotoxic response and their significance to man. Food Cosmet Toxicol 17(3):277–289

    Article  PubMed  CAS  Google Scholar 

  13. Gordi T, Nielsen E, Yu Z, Westerlund D, Ashton M (2000) Direct analysis of artemisinin in plasma and saliva using coupled-column high-performance liquid chromatography with a restricted-access material pre-column. J Chromatogr B Biomed Sci Appl 742(1):155–162

    Article  PubMed  CAS  Google Scholar 

  14. Green MD, Oturu EM, Tephly TR (1994) Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. Drug Metab Dispos 22(5):799–805

    PubMed  CAS  Google Scholar 

  15. Handschin C, Meyer UA (2003) Induction of drug metabolism: the role of nuclear receptors. Pharmacol Rev 55(4):649–673

    Article  PubMed  CAS  Google Scholar 

  16. Hien TT, White NJ (1993) Qinghaosu. Lancet 341(8845):603–608

    Article  PubMed  CAS  Google Scholar 

  17. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, Thu le TA, Hung NC, Pirmohamed M, Park BK, Edwards G (2002) Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos 30(9):1005–1012

    Article  PubMed  CAS  Google Scholar 

  18. Ingelman-Sundberg M (2004) Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 369(1):89–104

    Article  PubMed  CAS  Google Scholar 

  19. Iscan M, Rostami H, Guray T, Pelkonen O, Rautio A (1994) Interindividual variability of coumarin 7-hydroxylation in a Turkish population. Eur J Clin Pharmacol 47(4):315–318

    Article  PubMed  CAS  Google Scholar 

  20. Itoh M, Nakajima M, Higashi E, Yoshida R, Nagata K, Yamazoe Y, Yokoi T (2006) Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha. J Pharmacol Exp Ther 319(2):693–702

    Article  PubMed  CAS  Google Scholar 

  21. Kharasch ED, Hankins DC, Baxter PJ, Thummel KE (1998) Single-dose disulfiram does not inhibit CYP2A6 activity. Clin Pharmacol Ther 64(1):39–45

    Article  PubMed  CAS  Google Scholar 

  22. Kharasch ED, Hankins DC, Taraday JK (2000) Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity. Drug Metab Dispos 28(1):28–33

    PubMed  CAS  Google Scholar 

  23. Molander L, Lunell E, Andersson SB, Kuylenstierna F (1996) Dose released and absolute bioavailability of nicotine from a nicotine vapor inhaler. Clin Pharmacol Ther 59(4):394–400

    Article  PubMed  CAS  Google Scholar 

  24. Moran E, O’Kennedy R, Thornes RD (1987) Analysis of coumarin and its urinary metabolites by high-performance liquid chromatography. J Chromatogr 416(1):165–169

    PubMed  CAS  Google Scholar 

  25. Nakajima M, Yamagishi S, Yamamoto H, Yamamoto T, Kuroiwa Y, Yokoi T (2000) Deficient cotinine formation from nicotine is attributed to the whole deletion of the CYP2A6 gene in humans. Clin Pharmacol Ther 67(1):57–69

    Article  PubMed  CAS  Google Scholar 

  26. Nakajima M, Fukami T, Yamanaka H, Higashi E, Sakai H, Yoshida R, Kwon JT, McLeod HL, Yokoi T (2006) Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. Clin Pharmacol Ther 80(3):282–297

    Article  PubMed  CAS  Google Scholar 

  27. Oscarson M (2001) Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. Drug Metab Dispos 29(2):91–95

    PubMed  CAS  Google Scholar 

  28. Oscarson M, Gullsten H, Rautio A, Bernal ML, Sinues B, Dahl ML, Stengard JH, Pelkonen O, Raunio H, Ingelman-Sundberg M (1998) Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett 438(3):201–205

    Article  PubMed  CAS  Google Scholar 

  29. Pasanen M, Rannala Z, Tooming A, Sotaniemi EA, Pelkonen O, Rautio A (1997) Hepatitis A impairs the function of human hepatic CYP2A6 in vivo. Toxicology 123(3):177–184

    Article  PubMed  CAS  Google Scholar 

  30. Peamkrasatam S, Sriwatanakul K, Kiyotani K, Fujieda M, Yamazaki H, Kamataki T, Yoovathaworn K (2006) In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais. Drug Metab Pharmacokinetics 21(6):475–484

    Article  CAS  Google Scholar 

  31. Pelkonen O, Rautio A, Raunio H, Pasanen M (2000) CYP2A6: a human coumarin 7-hydroxylase. Toxicology 144(1–3):139–147

    Article  PubMed  CAS  Google Scholar 

  32. Poland RE, Pechnick RN, Cloak CC, Wan YJ, Nuccio I, Lin KM (2000) Effect of cigarette smoking on coumarin metabolism in humans. Nicotine Tob Res 2(4):351–354

    Article  PubMed  CAS  Google Scholar 

  33. Rautio A, Kraul H, Kojo A, Salmela E, Pelkonen O (1992) Interindividual variability of coumarin 7-hydroxylation in healthy volunteers. Pharmacogenetics 2(5):227–233

    Article  PubMed  CAS  Google Scholar 

  34. Ritschel WA, Brady ME, Tan HS, Hoffmann KA, Yiu IM, Grummich KW (1977) Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man. Eur J Clin Pharmacol 12(6):457–461

    Article  PubMed  CAS  Google Scholar 

  35. Shilling WH, Crampton RF, Longland RC (1969) Metabolism of coumarin in man. Nature 221(5181):664–665

    Article  PubMed  CAS  Google Scholar 

  36. Simonsson US, Jansson B, Hai TN, Huong DX, Tybring G, Ashton M (2003) Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9. Clin Pharmacol Ther 74(1):32–43

    Article  PubMed  CAS  Google Scholar 

  37. Simonsson US, Lindell M, Raffalli-Mathieu F, Lannerbro A, Honkakoski P, Lang MA (2006) In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Investig 36(9):647–653

    Article  CAS  Google Scholar 

  38. Sotaniemi EA, Rautio A, Backstrom M, Arvela P, Pelkonen O (1995) CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients. Br J Clin Pharmacol 39(1):71–76

    PubMed  CAS  Google Scholar 

  39. Svensson US, Ashton M (1999) Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol 48(4):528–535

    Article  PubMed  CAS  Google Scholar 

  40. Svensson US, Ashton M, Trinh NH, Bertilsson L, Dinh XH, Nguyen VH, Nguyen TN, Nguyen DS, Lykkesfeldt J, Le DC (1998) Artemisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 64(2):160–167

    Article  PubMed  CAS  Google Scholar 

  41. Xu P, Huang SL, Zhu RH, Han XM and Zhou HH (2002) Phenotypic polymorphism of CYP2A6 activity in a Chinese population. Eur J Clin Pharmacol 58(5):333–337

    Article  PubMed  CAS  Google Scholar 

  42. Zhang SQ, Hai TN, Ilett KF, Huong DX, Davis TM, Ashton M (2001) Multiple dose study of interactions between artesunate and artemisinin in healthy volunteers. Br J Clin Pharmacol 52(4):377–385

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Swedish International Development Cooperation Agency (SIDA/SAREC). The authors would like to thank Johan Birgersson and Anette Gummesson at Pfizer Consumer Healthcare, Helsingborg, Sweden for the analysis of nicotine and cotinine, and Achim Orzechowski, Annette Persson and Sveinn Briem at AstraZeneca R&D, Södertälje, Sweden for the analysis of coumarin and 7-hydroxycoumarin in plasma. We also thank Dr. Sabarinath Sreedharan Nair and the MSc students Niklas Nilsson, Anna Andersson and Martin Zakariasson for help with the analytical work. José Pedro Gil and Isabel Veiga are acknowledged for genotyping of CYP2A6 and Max Petzold for the statistical analysis. This study complies with the current laws of Sweden and Vietnam, where the research was performed.

Author information

Authors and Affiliations

  1. Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University, P.O. Box 431, 405 30, Göteborg, Sweden

    Sara Asimus & Michael Ashton

  2. National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam

    Trinh Ngoc Hai & Nguyen Van Huong

Authors
  1. Sara Asimus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Trinh Ngoc Hai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nguyen Van Huong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Ashton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Ashton.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Asimus, S., Hai, T.N., Van Huong, N. et al. Artemisinin and CYP2A6 activity in healthy subjects. Eur J Clin Pharmacol 64, 283–292 (2008). https://doi.org/10.1007/s00228-007-0406-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-007-0406-1

Keywords

Search

Navigation