Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine.
OBJECTIVE
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.
Britzi
Malka
M
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Perucca
Emilio
E
Soback
Stefan
S
Levy
René H
RH
Fattore
Cinzia
C
Crema
Francesca
F
Gatti
Giuliana
G
Doose
Dennis R
DR
Maryanoff
Bruce E
BE
Bialer
Meir
M
D000328:Adult; D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002220:Carbamazepine / Q000494:pharmacology*; D002853:Chromatography, Liquid / Q000295:instrumentation; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring; D004790:Enzyme Induction / Q000187:drug effects; D004867:Equipment Design; D005632:Fructose / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000295:instrumentation; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D014018:Tissue Distribution; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine