Hepatotrophic activity of benzodiazepine drugs in adult rats of either sex.

Adult rats with two-thirds of the liver removed were administered diets supplemented with benzodiazepine drugs over a period of 10 days and the mass of organ regenerated or the liver increment ascertained. For a number of the drugs, liver regeneration was stimulated; the effect was more consistent and reproducible in the adult female. On the basis of the lower sensitivity of the male, such animals provided an approach toward rating the hepatotrophic efficacy of the agents and in relation to structure. According to the current classification, hepatotrophic activity was higher with lorazepam, loprazolam, oxazepam and chlordiazepoxide; intermediate with nitrazepam, temazepam, quazepam, halazepam and triazepam and lower with diazepam, clorazepate dipotassium, clobazam and alprazolam. More reproducible responses in terms of g wet and dry liver per 100 g body weight were obtained with sham-operated or intact males. The antagonist, flumazenil, fed at 0.080% was not effective as such nor modified the responses in admixture with several drugs in partially hepatectomized or intact males. In vivo hepatic microsomal changes in protein, cytochrome P-450 or the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase with the various series were not remarkable or sporadic. Among other factors, the liver incremental changes noted currently are dependent on the metabolic intermediate benzodiazepines of varying elimination half-lives which may be distinct from that of the parent drug coupled with the alterations induced by partial ablation of the organ in rats of either sex.