An Overview of the Preclinical Aspects of Topiramate: Pharmacology, Pharmacokinetics, and Mechanism of Action

Authors

  • Richard P. Shank,

    Corresponding author
    1. The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A.
      Address correspondence and reprint requests to Dr. R. P. Shank at The R. W. Johnson Pharmaceutical Research Institute, Welsh & McKean Roads, Spring House, PA 19477, U.S.A.
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  • Joseph F. Gardocki,

    1. The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A.
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  • Anthony J. Streeter,

    1. The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A.
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  • Bruce E. Maryanoff

    1. The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A.
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Address correspondence and reprint requests to Dr. R. P. Shank at The R. W. Johnson Pharmaceutical Research Institute, Welsh & McKean Roads, Spring House, PA 19477, U.S.A.

Summary:

In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphory-lation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.

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