Single-Dose Kinetics of Primidone in Human Subjects : Effect of Phenytoin on Formation and Elimination of Active Metabolites of Primidone, Phenobarbital and Phenylethylmalonamide

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Effect of repetitive administration of phenytoin (PHT) on the single-dose pharmacokinetics of primidone (PRM) was investigated in 3 healthy male subjects. The peak concentration of unchanged PRM was achieved at 12 and 8 h after the administration of PRM in the absence and the presence of PHT, respectively. The elimination half-life of PRM was decreased from 19.4±2.2 (mean±S. E.) to 10.2±5.1 h (p<0.05) and the total body clearance was increased from 24.6±3.1 to 45.1±5.1 ml/h/kg (p<0.01) in the presence of PHT. No significant change was observed for the apparent volume of distribution between the two treatments. In the absence of PHT, the measurable amount (≦0.1 μmol/l) of phenobarbital (PB) and phenylethylmalonamide (PEMA) did not appear in the serum until 5.3 and 1.3 h after the PRM administration, and the peak concentrations of PB and PEMA were achieved at 52 and 36 h, but the concentrations of both metabolites were very low (PB 1.3 μmol/l ; PEMA 1.7 μmol/l). In the presence of PHT, within 0.8 and 0.5 h after the administration of PRM, the derived PB and PEMA appeared in the serum. About a 6-fold increase in the peak concentrations of both the metabolites were observed (PB 8.2 μmol/l ; PEMA 11.0 μmol/l). No significant changes were observed for the elimination half-lives of both PB and PEMA in the absence and presence of PHT. These results indicate that the induction of the enzyme system responsible for the oxidation of PRM to PB and PEMA mainly contribute to the alteration in the PRM disposition by PHT in the single-dose condition.
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Single-Dose Kinetics of Primidone in Human Subjects : Effect of Phenytoin on Formation and Elimination of Active Metabolites of Primidone, Phenobarbital and Phenylethylmalonamide

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