THE EFFECT OF DIPHENYL-PIPERAZINE COMPOUNDS AND OTHER AGENTS ON DIPHENYLHYDANTOIN, ZOXAZOLAMINE AND HEXOBARBITAL METABOLISM

¹ Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Mice pretreated for 4 days with a series of corm pounds were given 1 mg of diphenylhydantoin i.p. The quantity of diphenyihydantoin recovered at the end of 17 hr was significantly less in some of the pretreated animals compared with the controls. Compounds which were effective included a group of substituted diphenyl-piperazine agents (hydroxyzine, cyclizine, chlorcyclizine, meclizine and norchlorcyclizine), phenobarbital and diphenyihydantoin itself. 3-Methylcholanthrene and 3,4-benzpyrene, which were given as a single dose 24 hr before the diphenylhydantoin, were ineffective. Hydroxyzine pretreatment increased liver weight and total liver protein, and electron microscopy of the livers showed an increase in the smooth endoplasmic reticulum. Hydroxyzine pretreatment reduced hexobarbital sleeping time and zoxazolamine paralysis time in the mice. In vitro studies using the supernatant fraction containing the microsornes obtained after centrifugation at 9000 x g for 20 min showed an increased metabolism of hexobarbital and zoxazolamine. Human volunteers showed no change in diphenyihydantoin plasma half-life after 1 month of treatment with hydroxyzine.