title: Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Malka
authors.initials: M
authors.lastname: Britzi
authors.forename: Emilio
authors.initials: E
authors.lastname: Perucca
authors.forename: Stefan
authors.initials: S
authors.lastname: Soback
authors.forename: René H
authors.initials: RH
authors.lastname: Levy
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fattore
authors.forename: Francesca
authors.initials: F
authors.lastname: Crema
authors.forename: Giuliana
authors.initials: G
authors.lastname: Gatti
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Doose
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: 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
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine