title: A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy.
abstract: OBJECTIVE
  To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state.
  
  
  METHODS
  Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS).
  
  
  RESULTS
  No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug.
  
  
  CONCLUSIONS
  Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.
authors: Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors: Dorit
authors: D
authors: Mimrod
authors: Luigi M
authors: LM
authors: Specchio
authors: Malka
authors: M
authors: Britzi
authors: Emilio
authors: E
authors: Perucca
authors: Nicola
authors: N
authors: Specchio
authors: Angela
authors: A
authors: La Neve
authors: Stefan
authors: S
authors: Soback
authors: René H
authors: RH
authors: Levy
authors: Giuliana
authors: G
authors: Gatti
authors: Dennis R
authors: DR
authors: Doose
authors: Bruce E
authors: BE
authors: Maryanoff
authors: Meir
authors: M
authors: Bialer
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002220:Carbamazepine / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D000077236:Topiramate; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid