Inhibition of diphenylhydantoin metabolism in rats and in rat liver microsomes by antitubercular drugs

Abstract

Inhibition of of diphenylhydantoin metabolism by isonicotinic acid hydrazide [INH], para-amino salicylic acid [PAS], and cycloserine was studied in rats and in rat liver microsomal preparations. The studies in vivo suggested that inhibition followed a dose of 6 mg of INH per kg of body weight and that a gradually increasing degree of inhibition could be produced by increasing INH doses. The inhibition was manifested by an elevation of blood levels of diphenylhydantoin and prolongation of the duration of the elevated blood levels when compared with control animals receiving diphenylhydantoin alone. The studies in vitro revealed that parahydroxylation of diphenylhydantoin was inhibited by INH and PAS in a noncompetitive manner. INH was the most potent inhibitor (active in range of 10-5 M). Inhibition produced by combined addition of INH and PAS was greater than the sum of inhibitions obtained with the same concentrations of either drug alone.