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A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens

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Abstract

The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-’-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8–16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug–drug interactions is minimized.

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References

  1. White NJ (2004). Antimalarial drug resistance. J Clin Invest 113(8): 1084–1092

    CAS  PubMed  Google Scholar 

  2. Navaratnam V, Mansor SM, Sit NW, Grace J, Li Q and Olliaro P (2000). Pharmacokinetics of artemisinin-type compounds. Clin Pharmacokinet 39(4): 255–270

    Article  CAS  PubMed  Google Scholar 

  3. Svensson US, Ashton M, Trinh NH, Bertilsson L, Dinh XH and Nguyen VH et al (1998). Artemisinin induces omeprazole metabolism in human beings. Clin Pharmacol Ther 64(2): 160–167

    Article  CAS  PubMed  Google Scholar 

  4. Mihara K, Svensson US, Tybring G, Hai TN, Bertilsson L and Ashton M (1999). Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19. Fundam Clin Pharmacol 13(6): 671–675

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E and Avery BA et al (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  CAS  PubMed  Google Scholar 

  7. Asimus S, Elsherbiny D, Hai TN, Jansson B, Huong NV and Petzold MG et al(2007). Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects. Fundam Clin Pharmacol 21(3): 307–316

    Article  CAS  PubMed  Google Scholar 

  8. Hassan Alin M, Ashton M, Kihamia CM, Mtey GJ and Bjorkman A (1996). Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 90(1): 61–65

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. van Vugt M, Edstein MD, Proux S, Lay K, Ooh M, Looareesuwan S and Vugt M et al (1999). Absence of an interaction between artesunate and atovaquone–proguanil. Eur J Clin Pharmacol 55(6): 469–474

    Article  PubMed  Google Scholar 

  12. Giao PT, Vries PJde (2001). Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet 40(5): 343–373

    Article  CAS  PubMed  Google Scholar 

  13. WHO. Facts on ACTs (Artemisinin-based Combination Therapies). 2006 [cited 7 December 2007; Available from: http://www.rbm.who.int/cmc_upload/0/000/015/364/RBMInfosheet_9.htm

  14. Frye RF, Matzke GR, Adedoyin A, Porter JA and Branch RA (1997). Validation of the five-drug “Pittsburgh cocktail” approach for assessment of selective regulation of drug-metabolizing enzymes. Clin Pharmacol Ther 62(4): 365–376

    Article  CAS  PubMed  Google Scholar 

  15. Wedlund PJ, Aslanian WS, Jacqz E, McAllister CB, Branch RA and Wilkinson GR (1985). Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. J Pharmacol Exper Ther 234(3): 662–669

    CAS  Google Scholar 

  16. van der Weide J, Steijns LS (1999). Cytochrome P450 enzyme system: genetic polymorphisms and impact on clinical pharmacology. Ann Clin Biochem 36(Pt 6): 722–729

    PubMed  Google Scholar 

  17. Ko JW, Desta Z and Flockhart DA (1998). Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6. Drug Metab Dis 26(8): 775–778

    CAS  Google Scholar 

  18. Kupfer A, Patwardhan R, Ward S, Schenker S, Preisig R and Branch RA (1984). Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (nirvanol) in humans. J Pharmacol Exper Ther 230(1): 28–33

    CAS  Google Scholar 

  19. Kupfer A, Desmond PV, Schenker S and Branch RA (1982). Stereoselective metabolism and disposition of the enantiomers of mephenytoin during chronic oral administration of the racemic drug in man. J Pharmacol Exper Ther 221(3): 590–597

    CAS  Google Scholar 

  20. Beal SL, Sheiner LS. NONMEM user’s guides, GloboMax Inc., Hanover, Maryland, 1989—1998

  21. Jonsson EN and Karlsson MO (1999). Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58(1): 51–64

    Article  CAS  PubMed  Google Scholar 

  22. Jacqz E, Hall SD, Branch RA and Wilkinson GR (1986). Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin Phar Ther 39(6): 646–653

    Article  CAS  Google Scholar 

  23. Kerbusch T, Wahlby U, Milligan PA and Karlsson MO (2003). Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br J Clin Pharmacol 56(6): 639–652

    Article  CAS  PubMed  Google Scholar 

  24. Hassan M, Svensson US, Ljungman P, Bjorkstrand B, Olsson H and Bielenstein M et al (1999). A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. Br J Clin Pharmacol 48(5): 669–677

    Article  CAS  PubMed  Google Scholar 

  25. Holford N (2005) The Visual predictive check—superiority to standard diagnostic (Rorschach) Plots. Available from: http://www.page-meetingorg/?abstract=738. [cited PAGE 14; Abstr 738]

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

    Article  CAS  PubMed  Google Scholar 

  27. Chang M, Dahl ML, Tybring G, Gotharson E and Bertilsson L (1995). Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5(6): 358–363

    Article  CAS  PubMed  Google Scholar 

  28. Kupfer A, Bircher J and Preisig R (1977). Stereoselective metabolism, pharmacokinetics and biliary elimination of phenylethylhydantoin (Nirvanol) in the dog. J Pharmacol Exper Ther 203(3): 493–499

    CAS  Google Scholar 

  29. Roberts MS, Magnusson BM, Burczynski FJ and Weiss M (2001). Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41(10): 751–790

    Article  Google Scholar 

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Authors and Affiliations

  1. Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, P.O. Box 591, BMC, Uppsala, 751 24, Sweden

    Doaa A. Elsherbiny, Mats O. Karlsson & Ulrika S. H. Simonsson

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

    Sara A. Asimus & Michael Ashton

Authors
  1. Doaa A. Elsherbiny
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  2. Sara A. Asimus
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  3. Mats O. Karlsson
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  4. Michael Ashton
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  5. Ulrika S. H. Simonsson
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Correspondence to Doaa A. Elsherbiny.

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Elsherbiny, D.A., Asimus, S.A., Karlsson, M.O. et al. A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens. J Pharmacokinet Pharmacodyn 35, 203–217 (2008). https://doi.org/10.1007/s10928-008-9084-6

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  • DOI: https://doi.org/10.1007/s10928-008-9084-6

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