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Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine
Author(s) -
Britzi Malka,
Perucca Emilio,
Soback Stefan,
Levy René H.,
Fattore Cinzia,
Crema Francesca,
Gatti Giuliana,
Doose Dennis R.,
Maryanoff Bruce E.,
Bialer Meir
Publication year - 2005
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.0013-9580.2005.55204.x
Subject(s) - topiramate , metabolite , pharmacokinetics , urine , chemistry , pharmacology , carbamazepine , active metabolite , anticonvulsant , oral administration , metabolism , medicine , biochemistry , epilepsy , psychiatry
Summary: 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 ≥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.