Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine.

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Britzi M, Perucca E, Soback S, Levy RH, Fattore C, Crema F, Gatti G, Doose DR, Maryanoff BE, Bialer M

Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine.

Epilepsia. 2005 Mar;46(3):378-84. doi: 10.1111/j.0013-9580.2005.55204.x.

PubMed ID
15730535 [ View in PubMed
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Abstract

PURPOSE: To characterize the metabolic profile of topiramate (TPM) in humans and to assess the influence of enzyme induction by carbamazepine (CBZ) on the pharmacokinetics and metabolic profile of TPM. METHODS: Twelve healthy subjects received a single oral dose of TPM (200 mg) on two randomized occasions. On one occasion, TPM was administered alone, and on the other, it was given on day 18 of a 24-day treatment with CBZ (maintenance dosage, 600 mg/day). Blood and urine samples were collected for > or = 72 h after dosing. TPM and its metabolites were assayed in plasma and urine by a specific liquid chromatography-mass spectroscopy (LC-MS) method. RESULTS: Mean TPM oral clearance (CL/F) increased from 1.2 L/h (control) to 2.2 L/h after CBZ treatment. Mean TPM half-life decreased from 29 h to 19 h. TPM was excreted extensively in urine both under noninduced (56%) and CBZ-induced conditions (40%). 2,3-O-Des-isopropylidene-TPM (2,3-diol-TPM) was identified as the most prominent urinary metabolite, with a recovery accounting for 3.2% and 7.9% of the TPM dose under noninduced and induced conditions, respectively. Corresponding recovery values for 10-hydroxy-TPM (10-OH-TPM) were 1.2% and 1.8%, respectively. The control AUC(metabolite)/AUC(drug) ratio for 2,3-diol-TPM and 10-OH-TPM were 1.5% and 0.6%, and they increased by threefold and twofold, respectively, after CBZ treatment. CONCLUSIONS: TPM remains appreciably excreted unchanged in urine (41%) under CBZ-induced conditions, even though TPM CL/F increased by twofold. Although 2,3-diol-TPM and 10-OH-TPM were measured in unconjugated form, the significant increases in their AUC and urinary excretion are consistent with the twofold increase in TPM clearance.

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