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Much controversy surrounds the metabolism of phenytoin (5,5\u2010diphenylhydantoin), a widely used anticonvulsant, and an appropriate pharmacokinetic model to describe the disposition of this drug still lacks general acceptance. In the present study, metabolism of phenytoin in the isolated rat hepatocyte system was followed by assaying either the unchanged drug or the pooled metabolites in both the suspending medium and the cells. A model was developed which can describe the time course of the different species sampled. Inhibition of biotransformation by the major metabolic product [5\u2010(<jats:italic>p<\/jats:italic>\u2010hydroxyphenyl)\u20105\u2010phenylhydantoin or <jats:italic>p<\/jats:italic>\u2010HPPH] and the uptake and release of the latter were also studied, in order to elucidate the role of product inhibition in determining the dose\u2010dependent pharmacokinetic behavior of the drug. The results obtained strongly suggest that only concentrations of <jats:italic>p<\/jats:italic>\u2010HPPH higher than the ones attained by phenytoin biotransformation alone can significantly inhibit the main enzymatic reaction.<\/jats:p>","DOI":"10.1002\/bdd.2510050407","type":"journal-article","created":{"date-parts":[[2006,10,14]],"date-time":"2006-10-14T14:46:27Z","timestamp":1160837187000},"page":"357-376","source":"Crossref","is-referenced-by-count":1,"title":["A model describing the disposition of phenytoin in isolated rat hepatocytes"],"prefix":"10.1002","volume":"5","author":[{"given":"Jos\u00e9 A.","family":"Morais","sequence":"first","affiliation":[]},{"given":"John G.","family":"Wagner","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2006,2,7]]},"reference":[{"key":"e_1_2_1_2_2","first-page":"711","volume":"1","author":"Glazko A. J.","year":"1973","journal-title":"Drug Metab. 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