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Generation of statin drug metabolites through electrochemical and enzymatic oxidations

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Abstract

The generation of key drug metabolites for the purpose of their complete structural characterization, toxicity testing, as well as to serve as standards for quantitative studies, is a critical step in the pharmaceutical discovery and development cycle. Here, we utilized electrochemistry/mass spectrometry for the detection and subsequent generation of six phase I metabolites of simvastatin and lovastatin. Both simvastatin and lovastatin are widely used for the treatment of hypercholesterolemia. There are known drug–drug interaction issues of statin therapy, and it has been suggested that the oxidative metabolites may contribute to the cholesterol-lowering effect of both statins. Of the known phase I metabolites of simvastatin and lovastatin, none are commercially available, and chemical means for the synthesis of a very few of them have been previously reported. Here, we report that electrochemical oxidation of less than 1 mg each of simvastatin and lovastatin led to the generation of three oxidative metabolites of each parent to allow complete nuclear magnetic resonance characterization of all six metabolites. The yields obtained by the electrochemical approach were also compared with incubation of parent drug with commercially available bacterial mutant CYP102A1 enzymes, and it was found that the electrochemical approach gave higher yields than the enzymatic oxidations for the generation of most of the observed oxidative metabolites in this study.

Generation of statin drug metabolites by EC/MS (representative mass voltammogram shown), and recombinant CYP enzymes

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References

  1. Mauro VF (1993) Clin Pharmacokinet 24:195–202

    Article  CAS  Google Scholar 

  2. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J (1980) Proc Natl Acad Sci 77:3957–3961

    Article  CAS  Google Scholar 

  3. Jekkel A, Kónya A, Ilkóy E, Boros S, Horváth G, Sütó J (1997) J Antibiot 50:750–754

    Article  CAS  Google Scholar 

  4. Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, Ramjit HG, Pitzenberger SM, Stokker G, Duggan DE (1990) Drug Metab Dispos 18:476–483

    CAS  Google Scholar 

  5. Cheng H, Schwartz MS, Vickers S, Gilbert JD, Amin RD, Depuy B, Liu L, Rogers JD, Pond SM, Duncan CA, Olah TV, Bayne WF (1994) Drug Metab Dispos 22:139–142

    CAS  Google Scholar 

  6. Vickers S, Duncan CA, Chen IW, Rosegay A, Duggan DE (1990) Drug Metab Dispos 18:138–145

    CAS  Google Scholar 

  7. Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, Arison BH, Vyas KP (1997) Drug Metab Dispos 25:1191–1199

    CAS  Google Scholar 

  8. Vyas KP, Kari PH, Pitzenberger SM, Halpin RA, Ramjit HG, Arison B, Murphy JS, Hoffman WF, Schwartz MS, Ulm EH, Duggan DE (1990) Drug Metab Dispos 18:203–211

    CAS  Google Scholar 

  9. Greenspan MD, Yudkovitz JB, Alberts AW, Argenbright LS, Arison BH (1990) Smithson JL Drug Metab Dispos 16:678–682

    Google Scholar 

  10. Kim KH, Kang JY, Kim DH, Park SH, Kim D, Park KD, Lee YJ, Jung HC, Pan JG, Ahn T, Yun CH (2011) Drug Metab Dispos 39:140–150

    Article  CAS  Google Scholar 

  11. Stokker G (1994) Bioorg Med Chem Lett 4:1767–1770

    Article  CAS  Google Scholar 

  12. Baumann A, Karst U (2010) Expert Opin Drug Metab Toxicol 6:1–17

    Article  Google Scholar 

  13. Jahn S, Karst U (2012) J Chromatogr A 1259:16–49

    Article  CAS  Google Scholar 

  14. Jurva U, Wikström HV, Bruins AP (2000) Rapid Commun Mass Spectrom 14:529–533

    Article  CAS  Google Scholar 

  15. Jurva U, Wikström HV, Weidolf L, Bruins AP (2003) Rapid Commun Mass Spectrom 17:800–810

    Article  CAS  Google Scholar 

  16. Nouri-Nigjeh E, Permentier HP, Bischoff R, Bruins AP (2011) Anal Chem 83:5519–5525

    Article  CAS  Google Scholar 

  17. Madsen KG, Grönberg G, Skonberg C, Jurva U, Hansen SH, Olsen J (2008) Chem Res Toxicol 21:2035–2041

    Article  CAS  Google Scholar 

  18. Madsen KG, Skonberg C, Jurva U, Cornett C, Hansen SH, Johansen TN, Olsen J (2008) Chem Res Toxicol 21:1107–1119

    Article  CAS  Google Scholar 

  19. Thevis M, Lohmann W, Schrader Y, Kohler M, Bornatsch W, Karst U, Schänzer W (2008) Eur J Mass Spectrom 14:163–170

    Article  CAS  Google Scholar 

  20. Madsen KG, Olsen J, Skonberg C, Hansen SH, Jurva U (2007) Chem Res Toxicol 20:821–831

    Article  CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Chuck Li (Amgen Inc.) for developing the MATLAB script for recording mass-voltammograms, Chris Fotsch (Amgen Inc.) for the methodology used in this work to conduct the enzymatic incubations, Martin Eysberg, Jim Powers, and Joann Purkerson (Antec, USA) for training on the EC/MS platform as well as helpful discussions, and Nanosyn (Santa Clara, CA, USA) for performing the mass-directed metabolite purification of the dihydrodiol metabolites. We also acknowledge the Amgen Summer Internship program which made this manuscript possible.

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Correspondence to Smriti Khera.

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Khera, S., Hu, N. Generation of statin drug metabolites through electrochemical and enzymatic oxidations. Anal Bioanal Chem 405, 6009–6018 (2013). https://doi.org/10.1007/s00216-013-7021-z

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  • DOI: https://doi.org/10.1007/s00216-013-7021-z

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