TY - JOUR T1 - THE METABOLIC FATE OF DIPHENYLHYDANTOIN IN THE DOG, RAT AND MAN JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 275 LP - 284 VL - 130 IS - 3 AU - E. W. Maynert Y1 - 1960/11/01 UR - http://jpet.aspetjournals.org/content/130/3/275.abstract N2 - The metabolic fate of 5,5-diphenylhydantoin labeled in the 1-position with N15 was studied in rats and dogs. After intravenous administration of the drug to either species, more than 48 hours were required for the excretion of the isotope. A dog eliminated 80% of the intravenous dose of N15 in the urine, whereas rats excreted about 60% in the urine and 20% in the feces. Isotope dilution experiments revealed that rats eliminated 2% of an intravenous dose and 12% of an oral dose of diphenylhydantoin in the feces as unchanged drug. Only small amounts of N15 from the drug appeared in the ammonia and urea fractions of the urine of dogs. Furthermore, isotope dilution experiments with diphenylhydantoin, diphenylhydantoic acid and α-aminodiphenylacetic acid revealed that these compounds appear in urine only in traces. These findings are incompatible with the view advanced by others that diphenylhydantoin is primarily degraded by hydrolysis and that most of the drug is completely destroyed in the body. Various experiments indicated that dogs excreted 30 to 50% of a dose of diphenylhydantoin as glucuronic acid conjugates. Most of this urinary fraction could be accounted for by the glucuronide of 5-(p-hydroxyphenyl)-5-phenythydantoin (HPPH). A paper-chromatographic method was used to determine free HPPH, β-glucuronidase-released HPPH and acid-released HPPH in the urine of man, dog and the rat. In man and the dog less than 1% of the dose of diphenylhydantoin was excreted as free HPPH; however, rats excreted 2 to 4% of the dose as this compound. Acid-released HPPH accounted for 50% of the dose in man and the dog but only 20 to 25% in the rat. In the urine of all 3 species β-glucuronidase liberated about 75% as much HPPH as was released by acid. No HPPH was freed by phenol sulfatase. A number of experiments illustrated difficulties which can arise in a study of the metabolic fate of a drug which is very insoluble in water. The slow rate of excretion of metabolites after the intraperitoneal injection of diphenylhydantoin was found to be the result of crystallization of the drug within the peritoneal cavity. After oral administration the isotopic drug was absorbed very poorly compared with commercial preparations of diphenylhydantoin; this was explained by the larger size of the crystals in the isotopic preparation. ER -