Abstract
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.
Zusammenfassung
Bei holländischen gestreiften Kaninchen verursachte die Gravidität eine mehrmalige Senkung der mikrosomalen Biotransformation von Aminopyrin, Benzphetamin und Hexobarbital in vitro. Bei graviden Sprague-Dawley-Ratten zeigten verschiedene Bezugspunkte der Umwandlungsgeschwindigkeit von Hexobarbital in vitro (per mg mikrosomal Protein, per g Lebergewicht, 100 g Körpergewicht) eine unveränderte oder eine wenig erhöhte mikrosomale enzymatische Aktivität. Der Konzentrationsverlauf von Hexobarbital im Blut nach einer i. p. Applikation von 100 mg/kg NatriumHexobarbital bewies, daß das Schicksal von Hexobarbital nicht so sehr von kleinen Veränderungen der mikrosomalen enzymatischen Aktivität bestimmt wurde, als vielmehr durch Veränderungen in der Verteilung von Hexobarbital während der Gravidität. Verschiedene Bezugspunkte der Umwandlungsgeschwindigkeit von Anilin in vitro wiesen auf eine gesenkte oder unveränderte enzymatische Aktivität während der Gravidität hin, und Versuche in vivo zeigten, daß diese Veränderungen den Anilinmetabolismus in lebenden Ratten nicht beeinflußten. Die Ergebnisse bewiesen, daß die Gravidität einen signifikant verschiedenen Einfluß bei verschiedenen Tierarten auf den Metabolismus von Fremdstoffen ausübt. Eine Interpretation der Ergebnisse der Biotransformation in vitro auf lebendige Tiere wies darauf hin, daß mikrosomale enzymatische Aktivität oder Verteilung bei verschiedenen Stoffen eine minimale, oder anderseits, eine signifikante Rolle in der Beeinflussung deren Schicksals im Organismus haben kann.
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Supported in part by U.S. Public Health Grant NIGMS 12,675.
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Gut, I., Becker, B.A. & Gutová, M. Effect of pregnancy on hepatic microsomal drug metabolism in rabbits and rats. Arch Toxicol 35, 41–47 (1976). https://doi.org/10.1007/BF00333984
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DOI: https://doi.org/10.1007/BF00333984
Key words
- Microsomal drug metabolism
- Aminopyrine
- Benzphetamine
- Hexobarbital
- Aniline
- Pregnancy
- In vitro and in vivo
- Species