Molecular Pharmacology, Vol 18, 237-242, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Binding of Drugs to Human Serum Albumin

XIV. The Theoretical Basis for the Interaction between Phenytoin and Valproate1

¹ Department of Pharmaceutical Biochemistry, Biomedical Center, Uppsala University, Box 578, S-751 23 Uppsala, Sweden

The binding of valproate and phenytoin to human serum proteins has been studied qualitatively and quantitatively by equilibrium dialysis and with albumin immobilized in microparticles. Albumin was shown to be the only protein significantly binding valproate in serum. Valproate is bound to two sites on the albumin molecule, the diazepam and warfarin sites, with the association constants, K_a, 3.1 x 10⁴ M^-1. Phenytoin is bound primarily only to one site, (K_a 1.7 x 10⁴ M^-1), which is identical to the second valproate site, i.e., the warfarin one. A theoretical evaluation of the possible interaction between valproate and phenytoin in vivo was made. It was shown that valproate, with its high therapeutic plasma concentration, would increase the free fraction of phenytoin by 100%. On the other hand, phenytoin at therapeutic concentrations would not significantly displace valproate. These theoretical calculations were confirmed by the experimental results obtained with sera from epileptic patients treated with phenytoin. The binding of phenytoin was markedly decreased when valproate was added to the sera in vitro, while the binding of valproate was not significantly impaired.

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ACKNOWLEDGMENTS We thank Dr. Anders Eriksson, Boden, Sweden, for providing patient sera and Mr. Bo Creutzer, ERCO, Stockholm, for kind assistance. We also thank Mrs. Elisabet Tidare for skillful technical assistance.