Carbamazepine drug interactions: the influence of concurrent drug therapy on serum concentrations of carbamazepine and its epoxide metabolite

Abstract

The influence of concurrent drug therapy (phenytoin, valproate, phenobarbital, primidone) on serum concentrations of total and free carbamazepine (CBZ) and its active metabolite carbamazepine-10, 11-epoxide (CBZ-E) in 135 epileptic patients was studied. Serum CBZ and CBZ-E levels were analyzed by high performance liquid chromatography, whereas serum levels of the anticonvulsants were determined by fluorescence polarization immunoassay. Ultrafiltration was used to separate the free drugs from the protein-bound drugs in serum. Patients were divided into five groups according to the medication they received. Linear regression analyses revealed that concurrent drug therapy affected the metabolic rate of CBZ and CBZ-E in various ways. In patients on CBZ monotherapy, 78.3% of CBZ and 52.4% of CBZ-E were bound to plasma proteins. The total serum CBZ and CBZ-E concentrations significantly correlated with their respective free levels in serum. Compared with the CBZ monotherapy group, patients receiving concurrent drug therapy showed higher CBZ clearance and had elevated CBZ-E/CBZ ratios. Although the decrease in the total CBZ concentration depended on the simultaneous phenytoin and valproate concentrations (p less than 0.05), the serum levels of phenobarbital and primidone appeared to have no significant influence on the CBZ concentration. Since great interindividual variations were found in the serum concentration after a given dose, routine monitoring of the CBZ and CBZ-E serum concentrations is essential in designing a safe and effective therapeutic regimen for epileptic patients, especially for those on polytherapy.