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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
Author(s) -
Mimrod Dorit,
Specchio Luigi M.,
Britzi Malka,
Perucca Emilio,
Specchio Nicola,
Neve Angela La,
Soback Stefan,
Levy René H.,
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.1528-1167.2005.06805.x
Subject(s) - topiramate , pharmacokinetics , chemistry , carbamazepine , valproic acid , urine , pharmacology , anticonvulsant , metabolite , metabolism , urinary system , endocrinology , epilepsy , medicine , biochemistry , psychiatry
Summary: Purpose: 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.