Diphenylhydantoin stimulation of various pathways of hepatic microsomal drug metabolism in rabbits.
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Biomedical subjects
Publications and source records attributed to B A Becker.
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In Dutch-belted rabbits, pregnancy caused several-fold decrease of in vitro hepatic microsomal aminopyrine, benzphetamine, and hexobarbital biotransformations. In pregnant Sprague-Dawley rats, various kinds of expressing the in vitro rates of hexobarbital biotransformation (per mg of microsomal protein, g of liver, 100 g of body weight) indicated unchanged or slightly elevated microsomal enzyme activity. In vivo, the course of hexobarbital blood levels after i.p. hexobarbital sodium, 100 mg/kg, indicated that the fate of hexobarbital was not primarily determined by the small changes of microsomal enzyme activity but, rather, by changed hexobarbital distribution. Different ways of expressing in vitro rates of aniline biotransformation showed decreased or unchanged enzyme activity during pregnancy and in vivo experiments indicated that these changes did not affect aniline metabolism in living rats. The results pointed out marked species differences in the effect of pregnancy on drug metabolism. Interpretation of in vitro biotransformation data for living animals suggested that with different substrates, microsomal enzyme activity and distribution, respectively, may exert different effects playing either significant or apparently minor role in drug disposition.
Nature of considerable variability of hexobarbital sleeping time and drug metabolism efficiency within a single strain of rats were investigated. Wistar or Sprague-Dawley rats with shorter than average hexobarbital sleeping time had also higher rates of in vitro hepatic microsomal metabolism of hexobarbital, aminopyrine, aniline and benzene, higher liver weight, microsomal protein content and P-450 level, and faster hexobarbital blood level decline (but similar volumes of distribution) after intraperitoneal hexobarbital sodium than those with relatively longer hexobarbital sleeping time, but awakened with the same hexobarbital blood level. The differences were maintained throughout the life of rats and inherited in their offspring. It indicated a possible genetic control of hexobarbital sleeping time and efficiency of drug metabolisms with apparent differences in selection response for Type I and Type II substrates (hexobarbital and aminopyrine vs aniline): it might indicate different heredity mechanism for these types of substrates. Stronger hexobarbital narcotic effect in females was associated with the rate of hexobarbital metabolism, but also with higher brain sensitivity. Hexobarbital sleeping time pattern indicated more general pattern of drug metabolism (better for Type I substrates) and success of selection of rats for different efficiency of drug metabolism (up to 8-fold differences in F5 generation) suggested considerable genetic non-homogeneity of two common strains of laboratory rats.
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Eleven papers were compared for absorption of whey and for digestibility in vitro. Papers were squared, ground, and soaked in whey for 1, 5, and 15 min and for 1, 6, 24, 48, and 72 h. Digestibility in vitro was determined on minimum and maximum whey absorption of each squared and ground paper sample. Whey absorption by squared papers increased with time. Ground samples absorbed more whey than squared ones and maximum quantities were absorbed with 1 to 5 min. Mean percent absorptions for ground telephone book covers, glossy magazines, computer cards, computer printout sheets, daily newsprint, telephone directory yellow pages, cardboard box, feedsacks, brown bags, telephone directory white pages, and coasters were: 31.0, 35.2, 35.4, 36.5, 43.9, 47.9, 51.0, 51.4, 51.7, 55.6, and 67.4. For seven papers, addition of whey increased digestibility. Four papers were either unchanged or decreased in digestibility. This depression of digestibility may have resulted from the high fat content of whey used. Based on in vitro digestibilities, we conclude that it is possible to recycle selected paper/whey combinations through ruminants.
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Diphenylhydantoin sodium (DPH), 100 mg/kg/day for 3 days markedly induced aminopyrine, hexobarbital and aniline in vitro biotransformation, and increased P-450 level in microsomes and liver microsomal protein content in female and male rabbits. However, in pregnant rabbits, only aniline biotransformation was stimulated by DPH. In female nonpregnant rats, DPH also significantly stimulated in vitro hepatic biotransformation of aminopyrine, hexobarbital and aniline, and increased P-450 level in microsomes and liver to body weight ratio. In male rats, however, none of the pathways was stimulated significantly despite increases in P-450 level; the liver to body weight ratios were significantly increased. In day 15 pregnant rats only hexobarbital and in day 20 aminopyrine and aniline biotransformation were significantly increased by DPH-pretreatment. Responsiveness of hepatic microsomal enzymes in rats was apparently decreased on day 15 of pregnancy but was returning towards normal on day 20. Normal and DPH stimulated rates of biotransformation, and P-450 content of microsomes were higher in male than in female rats. These sex differences were not seen in rabbits. Rabbits of either sex generally responded to stimulation by DPH by substantially higher hepatic microsomal biotransformation rates than rats.
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