Advertisement

Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans

  • 248 Accesses

  • 16 Citations

Summary

The metabolism and excretion of 2,3:4,5-bis-0-(l-methylethylidene)-β-D-fructopyranose sulfamate (TOPAMAX®, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C] TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-methyl of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-methyl of the other isopropylidene, hydrolysis at the 2,3-{ie151-1}-isopropylidene, hydrolysis at the 4,5-{ie151-2}-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-{ie151-3}-isopropylidene group.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Waugh, J.; Goa, K. L. (2003). Topiramate: as monotherapy in newly diagnosed epilepsy. CNS Drugs 17(13), 985–992.

  2. 2.

    Maryanoff, B. E.; Nortey, S. O.; Gardocki, J. F.; Shank, R. P.; Dodgson, S. P. (1987). Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-0-(l-methylethylidene)-β-D-fructopyranose sulfamate and related compounds. J Med Chem, 30(5), 880–7.

  3. 3.

    Shank, R. P.; Gardocki, J. F.; Vaught, J. L.; Davis, C. B.; Schupsky, J. J.; Raffa, R. B.; Dodgson, S. J.; Nortey, S. O.; Maryanoff, B. E. (1994). Topiramate: Preclinical evaluation of a structurally novel anticonvulsant. Epilepsia, 35(2), 450–60.

  4. 4.

    Silberstein, S. D. (2003). Topiramate in migraine prevention. Expert Rev Neurotherapeutics, 3(6), 761–771.

  5. 5.

    Bays, H. E. (2004). Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obesity Research 12(8), 1197–1211.

  6. 6.

    Johnson, B. A. (2004). Uses of topiramate in the treatment of alcohol dependence. Expert Review of Neurotherapeutics 4(5), 751–758.

  7. 7.

    Kampman, K. M.; Pettinati, H.; Lynch, K. G.; Dackis, C; Sparkman, T.; Weigley, C.; O’Brien, C.P. (2004). A pilot trial of topiramate for the treatment of cocaine dependence. Drug and Alcohol Dependence 75(3), 233–240.

  8. 8.

    Bourgeois, B. F. D. (1999). Pharmacokinetics and metabolism of topiramate. Drugs of Today 35(1), 43–48.

  9. 9.

    Shank, R. P.; Gardocki, J. F.; Streeter, A. J.; Maryanoff, B. E. (2000). An overview of the preclinical aspects of topiramate: Pharmacology, Pharmacokinetics, and Mechanism of Action. Epilepsia 41 (Suppl. 1 ), S3-S9.

  10. 10.

    Streeter, A. J.; Stahle, P. L.; Holland, M. L.; Pritchard, J. F.; Takacs, A. R. (1995). Pharmacokinetics and bioavailability of topiramate in the beagle dog. Drug Metabolism and Disposition 23(1), 90–3.

  11. 11.

    Wu W. N., Heebner JB, Streeter AJ, Moyer, M.D., Takacs, A.R. (1994). Evaluation of the absorption, excretion, pharmacokinetics and metabolism of the anticonvulsant topiramate in healthy men. Pharm Res 11 (Suppl):S336.

  12. 12.

    Wu W. N., McKown L. A., Takacs A. R., Caldwell, G. W., Masucci, J. A., Gauthier, A. D., Jones, W. J., Nortey, S. O, Maryanoff, B.E., Ferraiolo, B. L. Metabolism of topiramate in mouse, rat, rabbit, dog and human. Proceedings of the 42nd ASMS Conference on Mass Spectrometry and Allied Topics 1994,59.

  13. 13.

    WuW.N., McKown L. A., Streeter A. J., Takacs A. R. Metabolism of TOPAMAX®: API (lonspray)-MS and MS/MS analysis of conjugated metabolites of TOPAMAX® (topiramate) in animals and humans. Proceedings of the 44th ASMS Conference on Mass Spectrometry and AlliedTopics 1996;244.

  14. 14.

    Nortey, S. O., Wu, Wu-Nan, Maryanoff, B.E. (1997). Synthesis of hydroxylated derivatives of topiramate, a no vel antiepileptic drug based on D-fructose: investigation of oxidative metabolites. Carbohydrate Research 304(1), 29–38.

  15. 15.

    Miller, J.C; Miller, J.N. (1992). Statistics for analytical chemistry, 2nd Edition, Ellis Hardwood Limited, West Sussex, England.

  16. 16.

    Caldwell, G. W., Sorgi, K. L. Scott, L., Maryanoff, B. E., Maryanoff, C. A., Masucci, J.A., Nortey, S. O., Siscoj W. R., Micheel, A., Ko, Y. (1989). The Electron Ionization Mass Spectra of Novel 2,3:4,5-Bis-{ie164-1}-(l-methyl-ethylideneJ-β-D-Fructospyranose Derivatives and Related Sugar Sulfamates, Organic Mass Spectra 24 (12), 1051–1059.

Download references

Author information

Correspondence to G. W. Caldwell.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Caldwell, G.W., Wu, W.N., Masucci, J.A. et al. Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans. European Journal of Drug Metabolism and Pharmacokinetics 30, 151–164 (2005). https://doi.org/10.1007/BF03190614

Download citation

Keywords

  • Animals
  • excretion
  • metabolism
  • 2, 3:4,5-bis-0-(l-methylethylidene)-β-D-fructopyranose sulfamate
  • humans
  • Topiramate
  • TOPAMAX®.