Biopharmaceutical studies on hydantoin derivatives. I. Physico-chemical properties of hydantoin derivatives and their intestinal absorption.

Authors:
  • HFHiroshi Fujioka
    Hiroshi Fujioka
  • TTTakashi Tan
    Takashi Tan
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Abstract
The physico-chemical properties of a series of hydantoin derivatives [anticonvulsants] and their intestinal absorption from solution in rats were studied. The introducton of the benzenesulfonyl group at the 1-position of the hydantoin ring greatly affects the physico-chemical properties: the acid dissociation constants were increased 1000-fold and the partition coefficients were increased 100- to 1000-fold in the chloroform/H2O system and 10- to 100-fold in the n-octanol/H2O system. The solubilities of 1-benzenesulfonylhydantoin derivatives increased with increasing pH of the solution at pH > 5, but the solubilities of the 1-unsubstituted hydantoin derivatives were scarcely dependent on the pH of the solution in the pH 1-8 region. The intestinal absorption from solution was caused by the passive transport according to the 1st-order kinetics. The absorption rate constants of 1-benzene-sulfonylhydantoin derivatives were large even under the condition where they were 99% ionized in the solution than that of the corresponding 1-unsubstituted hydantoin derivatives which exist mainly as the un-ionized form under the same condition. The intestinal absorption from a solution and the partitioning to chloroform produced linear free energy relationships to each other for the 1-benzenesulfonylhydantoin derivatives and for the 1-unsubstituted hydantoin derivatives independently. When the partition coefficients in the n-octanol/H2O system were applied, the hydroxyl derivatives deviated from linear relationships. The in vivo behavior and the bioavailability are discussed.