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Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid

  • Pharmacokinetics and Disposition
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Abstract

Objective

The aim of this study was to examine the effect of carbamazepine on the pharmacokinetics of orally administered simvastatin in healthy volunteers.

Methods

In a randomised, two-phase crossover study and a wash out of 2 weeks, 12 healthy volunteers took carbamazepine for 14 days (600 mg daily except 200 mg daily for the first 2 days) or no drug. On day 15, each subject ingested 80 mg simvastatin. Serum concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 24 h.

Results

Carbamazepine decreased the mean total area under the serum concentration–time curve of simvastatin and simvastatin acid by 75% (P<0.001) and 82% (P<0.001), respectively. The mean peak concentrations of both simvastatin and simvastatin acid were reduced by 68% (P<0.01), and half-life of simvastatin acid was shortened from 5.9±0.3 h to 3.7±0.5 h (P<0.01) by carbamazepine.

Conclusion

Carbamazepine greatly reduces the serum concentrations of simvastatin and simvastatin acid, probably by inducing their metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided or the dose of simvastatin should be considerably increased.

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References

  1. Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ et al (1997) In vitro metabolism of simvastatin in humans [SBT] identification of metabolizing enzymes and effect of the drug on hepatic P 450s. Drug Metab Dispos 25:1191–1199

    CAS  PubMed  Google Scholar 

  2. Landrum Michalets E (1998) Review of therapeutics. Pharmacotherapy18:84–112

  3. Laroudie C, Salazar DE, Cosson JP, Cheuvart B, Istin B, Girault J et al (2000) Carbamazepine-nefazodone interaction in healthy subjects. J Clin Psychopharmacol 20:46–53

    Article  CAS  PubMed  Google Scholar 

  4. Villikka K, Kivistö KT, Mäenpää H, Joensuu H, Neuvonen PJ (1999) Cytochrome P 450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors. Clin Pharmacol Ther 66:589–593

    CAS  PubMed  Google Scholar 

  5. Eap CB, Yasui N, Kaneko S, Baumann P, Powell K, Otani K (1999) Effects of carbamazepine coadministration on plasma concentrations of the enantiomers of mianserin and its metabolites. Ther Drug Monit 21:166–170

    Article  CAS  PubMed  Google Scholar 

  6. Lucas RA, Gilfillan DJ, Bergstom RF (1988) A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism. Eur J Pharmacol 54:639–643

    Google Scholar 

  7. Jerling M, Lindström L, Bondesson U, Bertilsson L (1994) Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 16:368–374

    CAS  PubMed  Google Scholar 

  8. Pirmohamed M, Kitteringham NR, Breckenridge AM, Park BK (1992) The effect of the enzyme induction on the cytochrome P 450-mediated bioactivation of carbamazepine by mouse liver microsomes. Biochem Pharmacol 44:2307–2314

    CAS  PubMed  Google Scholar 

  9. Kantola T, Kivistö KT, Neuvonen PJ (1998) Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 64:177–182

    Google Scholar 

  10. Neuvonen PJ, Kantola T, Kivistö KT (1998) Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther 63:3332–3341

    Google Scholar 

  11. Arnadottir M, Eriksson LO, Thysell H, Karkas JD (1993) Plasma concentration profiles of simvastatin 3-hydroxy-3-metyl-glutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without cyclosporin. Nephron 65:410–413

    CAS  PubMed  Google Scholar 

  12. Kantola T, Kivistö KT, Neuvonen PJ (1998) Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 64:58–65

    CAS  PubMed  Google Scholar 

  13. Segaert MF, De-Soete C, Vandewiele I, Verbanck J (1996) Drug-interaction-induced rhabdomyolysis. Nephrol Dial Transplant 11:1846–1847

    CAS  PubMed  Google Scholar 

  14. Wu CY, Benet LZ, Hebert MF, Gupta SK, Rowland M, Gomez DY et al (1995) Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine. Clin Pharmacol Ther 58:492–497

    CAS  PubMed  Google Scholar 

  15. Backman JT, Kyrklund C, Kivistö KT, Wang JS, Neuvonen PJ (2000) Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 68:122–129

    Google Scholar 

  16. Pichard L, Domergue J, Fourtanier G, Koch P, Schran HF, Maurel P (1996) Metabolism of the new immunosuppressor cyclosporin G by human liver cytochromes P 450. Biochem Pharmacol 51:591–598

    Article  CAS  PubMed  Google Scholar 

  17. Kogan AD, Orensterin S (1990) Lovastatin-induced acute rhabdomyolysis. Postgrad Med J 66:293–296

    Google Scholar 

  18. Duell PB, Connor WE, Illingworth DR (1998) Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol 81:368–369

    CAS  PubMed  Google Scholar 

  19. Schmassmann-Suhijar D, Bullingham R, Gasser R, Schmutz J, Haefeli WE (1998) Rhabdomyolysis due to interaction of simvastatin with mibefradil. Lancet 351:1929–1930

    CAS  PubMed  Google Scholar 

  20. Jacobson RH, Wang P, Glueck CJ (1997) Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone (letter) JAMA 277:296–297

    Google Scholar 

  21. Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ (2000) Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 68:592–597

    Article  CAS  PubMed  Google Scholar 

  22. Bertilsson L, Tybring G, Widen J, Chang M, Tomson T (1997) Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19. Br J Pharmacol 44:186–189

    Article  CAS  Google Scholar 

  23. Tateishi T, Masako A, Nakura H, Watanabe M, Tanaka M, Kumai T, Kobayashi S (1999) Carbamazepine induces multiple cytochrome P 450 subfamilies in rats. Chemico-Biological Interactions117:257–268

    Google Scholar 

  24. Baciewicz AM (1986) Carbamazepine drug interaction. Ther Drug Monit 8:305–317

    CAS  PubMed  Google Scholar 

  25. Iwahashi K, Miyatake R, Suwaki H, Hosokawa K, Ichikawa Y (1995) The drug–drug interaction effects of haloperidol on plasma carbamazepine levels. Clin Neuropharmacol 18:233–236

    CAS  PubMed  Google Scholar 

  26. Jerling M, Lindström L, Bondesson U, Bertilsson L (1994) Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 16:368–374

    CAS  PubMed  Google Scholar 

  27. Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS et al (1995) Carbamazepine but not valproate induces bupropion metabolism. J Clin Psychopharmacol 15:327–333

    Article  CAS  PubMed  Google Scholar 

  28. Bertilsson L, Höjer B, Tybring G, Osterloh J, Rane A (1980) Autoinduction of carbamazepine metabolism in children studied with a stabile isotope technique. Clin Pharmacol Ther 27:83–88

    CAS  PubMed  Google Scholar 

  29. McNamara PJ, Colburn WA, Gibaldi M (1979) Time course of carbamazepine self-induction. J Pharmocokinet Biopharm 7:63–68

    CAS  Google Scholar 

  30. Pitlick WH, Levy RH (1977) Time-dependent kinetics I: exponential autoinduction of carbamazepine in monkeys. J Pharm Sci 66:647–649

    CAS  PubMed  Google Scholar 

  31. Pitlick WH, Levy RH, Troupin AS, Green JR (1976) Pharmacokinetic model to describe self-induced decreases in steady-state concentrations of carbamazepine. J Pharm Sci 65:462–463

    CAS  PubMed  Google Scholar 

  32. Mikati MA, Browne TR, Collin JF (1989) Time course of carbamazepine autoinduction. The VA Cooperative Study No.118 Group. Neurology 39:592–594

    CAS  PubMed  Google Scholar 

  33. Scheyer RD, Cramer JA, Mattson RH (1994) A pharmacodynamic approach to the estimate of carbamazepine autoinduction. J Pharm Sci 84:491–494

    Google Scholar 

  34. Murphy MJ, Dominiczak MH (1999) Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med J 75:359–360

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Ms. Kerstin Granberg for excellent technical assistance. Supported by grants from the Faculty of Medicine, University of Umeå and scientific council of Jönköping, Sweden, and the Helsinki University Central Hospital Research Fund and the National Technology Agency (Tekes), Finland.

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Correspondence to T. Mjörndal.

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Ucar, M., Neuvonen, M., Luurila, H. et al. Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid. Eur J Clin Pharmacol 59, 879–882 (2004). https://doi.org/10.1007/s00228-003-0700-5

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  • DOI: https://doi.org/10.1007/s00228-003-0700-5

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