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Time-dependent interaction between phenytoin and valproic acid

Laboratory of Neuropharmacology (Drs. Riva, Albani, Contin, Ambrosetto, Gobbi, Santucci, Procaccianti, and Baruzzi), Institute of Neurology, University of Bologna, and the Institute of Medical Pharmacology (Dr. Perucca), University of Pavia, Italy.

The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p < 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 ± 2.3% versus 8.3 ± 1.9%; p < 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p < 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.

Address correspondence and reprint requests to Dr. Riva, Institute of Neurology, Via Foscolo 7, 40123 Bologna, Italy.

This work has been exeruted as a part of the "Progetto Finalizzato Medicina Preventiva e Riabilitativa" of the National Research Council of Italy, Grant No. 83.02528.56.

Accepted for publication July 9, 1984.