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.
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.
Mimrod
Dorit
D
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Specchio
Luigi M
LM
Britzi
Malka
M
Perucca
Emilio
E
Specchio
Nicola
N
La Neve
Angela
A
Soback
Stefan
S
Levy
René H
RH
Gatti
Giuliana
G
Doose
Dennis R
DR
Maryanoff
Bruce E
BE
Bialer
Meir
M
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
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid