Skip to main content
SpringerLink
Log in

Pharmacokinetic Interactions with Felbamate

In Vitro-In Vivo Correlation

  • Review Article
  • Drug Interactions
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Summary

This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism.

In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions.

Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it has been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate.

Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of β-oxidation.

No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate’s drug: drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.

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.

Similar content being viewed by others

References

  1. Holmes GB, Graves NM, Leppik IE, et al. Felbamate: bidirectional effects on phenytoin and carbamazepine serum concentrations [abstract]. Epilepsia 1987; 28: 578

    Article  Google Scholar 

  2. Sheridan PH, Ashworth M, Milne K, et al. Open pilot study of felbamate (ADD 03055) in partial seizures [abstract]. Epilepsia 1986; 27 Suppl.: 649

    Google Scholar 

  3. Wilensky AJ, Friel PN, Ojemann LM, et al. Pharmacokinetics of W-554 (ADD 03055) in epileptic patients. Epilepsia 1985; 26: 602–6

    Article  PubMed  CAS  Google Scholar 

  4. Wagner ML, Graves NM, Marienau K, et al. Discontinuation of pheytoin and carbamazepine in patients receiving felbamate. Epilepsia 1991; 32: 398–406

    Article  PubMed  CAS  Google Scholar 

  5. Schumaker RC, Fantel C, Kelton E, et al. Evaluation of the elimination of 14C felbamate in healthy men [abstract]. Epilepsia 1990; 31Suppl. 5: 642

    Google Scholar 

  6. Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 1995; 36Suppl. 5: S8–13

    Article  PubMed  Google Scholar 

  7. Kunze KL, Wienkers LC, Thummel KE, et al. Warfarin-fluconazole I: inhibition of the human cytochrome P450-de-pendent metabolism of warfain by fluconazole: in vitro studies. Drug Metab Dispos 1996; 34: 412–21

    Google Scholar 

  8. Robson RA, Metthews AP, Miners JO, et al. Characterization of theophylline metabolism in human liver microsomes. Br J Clin Pharmacol 1987; 24: 293–300

    Article  PubMed  CAS  Google Scholar 

  9. Miles JS, McLaren AW, Forrester LM, et al. Identification of human liver cytochrome P450 responsible for coumarin 7-hy-droxylase activity. Biochem J 1990; 267: 365–71

    PubMed  CAS  Google Scholar 

  10. Rettie AE, Eddy AC, Heimark LD, et al. Characteristics of warfarin hydroxylation catalyzed by human liver microsomes. Drug Metab Dispos 1989; 17: 265–70

    PubMed  CAS  Google Scholar 

  11. Wrighton SA, Stevens JC, Becker GW, et al. Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytion 4′-hydroxylation. Arch Biochem Biophys 1993; 306: 1–6

    Article  Google Scholar 

  12. Goldstein JA, Faletto MB, Romkes-Sparks R, et al. Evidence that CYP2C19 is the major (S)-mephenytoin 4′-hydroxylase in humans. Biochemistry 1994; 33: 1743–52

    Article  PubMed  CAS  Google Scholar 

  13. Boobis AR, Murray S, Hampden CE, et al. Genetic polymorphisms in drug oxidation: in vitro studies of human debrisoquine 4-hydroxylase and bufuralol l′-hydroxylase activities. Biochem Pharmacol 1985; 34: 65–71

    Article  PubMed  CAS  Google Scholar 

  14. Kronbach T, Mathys D, Catin T, Meyer UA. High-performance liquid Chromatographic assays for bufuralol l′-hydroxylase and dextromethorphan O-demethylation in microsomes and purified cytochrome P450 isozymes of human liver. Analytical Biochem 1987; 162: 24–32

    Article  CAS  Google Scholar 

  15. Yamazaki H, Guo Z, Pensmark M, et al. Bufuralol hydroxylation by cytochrome P450 2D6 and 1A2 enzymes in human liver. Mol Pharmacol 1994; 46: 568–77

    PubMed  CAS  Google Scholar 

  16. Reinke LA, Moyer MJ. p-Nitrophenol hydroxylation: a microsomal oxidation which is highly inducible by ethanol. Drug Metab Dispos 1985; 13: 548–52

    PubMed  CAS  Google Scholar 

  17. Lawrence RF, Rettie AE, Eddy AC, et al. Chemical synthesis, absolute configuration and stereochemistry of formation of 10-hydroxy warfarin: a major oxidative metabolite of (+)-(R)-warfarin from hepatic microsomal preparations. Chirality 1990; 2: 96–105

    Article  PubMed  CAS  Google Scholar 

  18. Reidenberg P, Glue P, Banfield C, et al. Pharmacokinetic interaction studies between felbamate and vigabatrin. Br J Clin Pharmacol 1995; 40: 157–60

    Article  PubMed  CAS  Google Scholar 

  19. Carter-Wallace study 41, data on file

  20. Wagner ML, Graves NM, Leppik IE, et al. The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994; 56: 494–502

    Article  PubMed  CAS  Google Scholar 

  21. Hooper WD, Franklin ME, Glue P, et al. Effects of felbamate on valproic acid disposition in healthy volunteers: inhibition of β-oxidation. Epilepsia 1996; 37: 91–7

    Article  PubMed  CAS  Google Scholar 

  22. Saano V, Glue P, Banfield C, et al. Effects of felbamate on the pharmacokinetics of a low dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58: 523–31

    Article  PubMed  CAS  Google Scholar 

  23. Montgomery PA, Sachdeo RJ, Narang-Sachdeo SK, et al. Felbamate pharmacokinetics after coadministration of erythromycin [abstract]. Epilepsia 1994; 35Suppl. 8: 113

    Google Scholar 

  24. Colucci R, Glue P, Holt B, et al. Effects of felbamate on the pharmacokinetics of lamotrigine. J Clin Pharmacol 1996; 36: 634–8

    PubMed  CAS  Google Scholar 

  25. Colucci R, Glue P, Reidenberg P, et al. Effects of felbamate on the pharmacokinetics of clonazepam. Am J Ther 1996; 3: 294–7

    Article  PubMed  Google Scholar 

  26. Hulsman JARJ, Rentmeester ThW, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of the mono- and dihydroxy metabolites of oxcarbazepine. Clin Pharmacol Ther 1995; 58: 383–9

    Article  PubMed  CAS  Google Scholar 

  27. Reidenberg P, Glue P, Banfield C, et al. Effects of felbamate on the pharmacokinetics of phenobarbital. Clin Pharmacol Ther 1995; 58: 279–87

    Article  PubMed  CAS  Google Scholar 

  28. Albani F, Theodore WH, Washington P, et al. Effect of felbamate on plasma levels of carbamazepine and its metabolite. Epilepsia 1991; 32: 130–2

    Article  PubMed  CAS  Google Scholar 

  29. Sachdeo RC, Padela MF. The effect of felbamate on phenobarbital serum concentrations [abstract]. Epilepsia 1994; 35Suppl. 8: 94

    Google Scholar 

  30. Kudriakova TB, Sirota LA, Rozova GI, et al. Autoinduction and steady-state pharmacokinetics of carbamazepine and its major metabolites. Br J Clin Pharmacol 1992; 33: 611–5

    Article  PubMed  CAS  Google Scholar 

  31. Waxman DJ, Azaroff L. Phenobarbital induction of cytochrome P-450 gene expression. Biochem J 1992; 281: 577–92

    PubMed  CAS  Google Scholar 

  32. Shaw PM, Barnes TS, Cameron D, et al. Purification and characterization of an anticonvulsant-induced human cytochrome P-450 catalysing cyclosporin metabolism. Biochem J 1989; 263: 653–63

    PubMed  CAS  Google Scholar 

  33. Werk EE, MacGee J, Sholiton LJ. Effect of diphenylhydantoin on cortisol metabolism in man. J Clin Invest 1964; 43: 1824–34

    Article  PubMed  CAS  Google Scholar 

  34. Banfield C, Zhu GR, Jen F, et al. The effects of age on the clearance of felbamate: a retrospective analysis using nonlinear mixed effects modeling. Ther Drug Monit 1996; 18: 19–29

    Article  PubMed  CAS  Google Scholar 

  35. Kelley MT, Walson PD, Cox S. Population kinetics of felbamate in children [abstract]. Clin Pharmacol Ther 1996; 59: 213

    Article  Google Scholar 

  36. Guengerich FP. Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs. Am J Obstet Gynecol 1990; 163: 2159–63

    PubMed  CAS  Google Scholar 

  37. Purba HS, Maggs JL, Orme ML’E, et al. The metabolism of 17α-ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites. Br J Clin Pharmacol 1987; 23: 447–53

    Article  PubMed  CAS  Google Scholar 

  38. Fuerst RH, Graves NM, Leppik IE, et al. Felbamate increases phenytoin but decreases carbamezepine concentrations. Epilepsia 1988; 29: 488–91

    Article  PubMed  CAS  Google Scholar 

  39. Leppik IE, Dreifuss FE, Pledger GW, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991; 41: 1785–9

    Article  PubMed  CAS  Google Scholar 

  40. Sachdeo R, Wagner M, Sachdeo S, et al. Steady-state pharmacokinetics of phenytoin when coadministered with felbatol [abstract]. Epilepsia 1992; 33Suppl. 3: 84

    Google Scholar 

  41. Schering Plough study 193–162, data on file

  42. Bajpai M, Roskos RK, Shen DD, et al. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Monit Dispos 1996; 24: 1401–3

    CAS  Google Scholar 

  43. Gidal BE, Zupanc ML. Potential pharmacokinetic interaction between felbamate and phenobarbital. Ann Pharmacother 1994; 28: 455–8

    PubMed  CAS  Google Scholar 

  44. Kerrick JM, Wolff DL, Risinger MW, et al. Increased phenobarbital plasma concentrations after felbamate initiation [abstract]. Epilepsia 1994; 35Suppl. 8: 96

    Google Scholar 

  45. Delgado MR. Changes in valproic acid concentrations and dose/level ratios by felbamate coadministration in children [abstract]. Ann Neurol 1994; 36: 538

    Google Scholar 

  46. Patrias J, Espe-Lillo J, Ritter FJ. Felbamate-methsuximide interaction [abstract]. Epilepsia 1992; 33Suppl. 3: 84

    Google Scholar 

  47. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Biochem Pharmacol 1994; 47: 1969–79

    Article  PubMed  CAS  Google Scholar 

  48. Graves NM, Holmes GB, Fuerst RH, et al. Effect of felbamate on phenytoin and carbamazepine serum concentrations. Epilepsia 1989; 30: 225–9

    Article  PubMed  CAS  Google Scholar 

  49. Theodore WH, Raubertas RF, Porter RJ, et al. Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991; 32: 392–7

    Article  PubMed  CAS  Google Scholar 

  50. Howard JR, Dix RK, Shumaker RC, et al. The effects of felbamate on carbamazepine pharmacokinetics [abstract]. Epilepsia 1992; 33Suppl. 3: 84–5

    Google Scholar 

  51. Wagner ML, Remmel RP, Graves NM, et al. Effect of felbamate on carbamazepine and its major metabolites. Clin Pharmacol Ther 1993; 53: 536–43

    Article  PubMed  CAS  Google Scholar 

  52. Guengerich FP. Oxidation of 17α-ethinylestradiol by human liver cytochrome P450. Mol Pharmacol 1988; 33: 500–8

    PubMed  CAS  Google Scholar 

  53. Guengerich FP. Characterization of human microsomal cytochrome P-450 enzymes. Annu Rev Pharmacol Toxicol 1989; 29: 241–64

    Article  PubMed  CAS  Google Scholar 

  54. Fitton A, Goa KL. Lamotrigine. Drugs 1995; 50: 691–713

    Article  PubMed  CAS  Google Scholar 

  55. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibition of desipramine hydroxylation in vitro by serotonin reuptake inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J Pharmacol Exper Ther 1994; 268: 1278–83

    Google Scholar 

  56. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibitors of alprazolam metabolism by serotonin reuptake inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994; 38: 23–31

    Article  CAS  Google Scholar 

  57. von Moltke LL, Greenblatt DJ, Harmatz LS, et al. Cytochromes in psychopharmacology. J Clin Psychopharmacol 1994; 14: 1–4

    Google Scholar 

  58. von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995; 15: 125–31

    Article  Google Scholar 

  59. von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exper Ther 1996; 276: 370–9

    Google Scholar 

  60. Black DJ, Kunze KL, Wienkers LC, et al. Warfarin-fluconazole II: a metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996; 34: 422–8

    Google Scholar 

  61. Kunze KL, Trager WF. Warfarin-fluconazole III: a rational approach to management of a metabolically based drug interaction. Drug Metab Dispos 1996; 34: 429–35

    Google Scholar 

  62. Bopp BA, Nequist GE, Rodrigues AD. Role of the cytochrome P450 3A subfamily in the metabolism of (14C)tiagabine by huan hepatic microsomes [abstract]. Epilepsia 1995; 36Suppl. 3: S159

    Google Scholar 

  63. Bourgeois BFD. Drug interaction profile of topiramate. Epilepsia 1996; 37Suppl. 2: S14–7

    Article  PubMed  CAS  Google Scholar 

  64. Glue P, Banfield C. Psychiatry, Psychopharmacology and P-450s. Human Psychopharmacol 1996; 11: 97–114

    Article  CAS  Google Scholar 

  65. Bun H, Monjanel-Mouterde S, Noel F, et al. Effects of age and antiepileptic drugs on plasma levels and kinetics of clobazam and N-desmethylclobazam. Pharmacol Toxicol 1990; 67: 136–40

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Pharmacology, Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-4, 4455, Kenilworth, New Jersey, 033-0539, USA

    Paul Glue & Christopher R. Banfield

  2. Wallace Laboratories, Cranford, New Jersey, USA

    James L. Perhach

  3. Department of Pharmacology, University of Washington, Seattle, Washington, USA

    Gary G. Mather, Jagdish K. Racha & Rene H. Levy

Authors
  1. Paul Glue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher R. Banfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James L. Perhach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gary G. Mather
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jagdish K. Racha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rene H. Levy
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glue, P., Banfield, C.R., Perhach, J.L. et al. Pharmacokinetic Interactions with Felbamate. Clin. Pharmacokinet. 33, 214–224 (1997). https://doi.org/10.2165/00003088-199733030-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-199733030-00004

Keywords

Search

Navigation