Hexobarbital metabolism

In vitro, chloroform is metabolized 10 times faster by kidney microsomes from male compared with female mice. In contrast to rats, male mice given hexobarbital metabolize it more slowly, and the pharmacological effect is more prolonged than in females. The excretion... 

Age (days) Percent hexobarbital metabolized in vitrrf in 1 hr (guinea pigs) Percent hexobarbital metabolized in vivo in 3 hr (mice) Sleeping time in mice (min) ... 

T reatment Hexobarbital metabolism (nmol min-1 mg-1) Sleeping time (min)... 

Although in some animals starvation appears to have effects similar to those of protein deficiency, this is not necessarily the case. For example, in the mouse, monooxygenation is decreased but reduction of p-nitrobenzoic acid is unaffected. In male rats, hexobarbital and pentobarbital hydroxylation as well as aminopyrine A-demethylation are decreased, but aniline hydroxylation is increased. All of these activities are stimulated in the female. Water deprivation in gerbils causes an increase in P450 and a concomitant increase in hexobarbital metabolism, which is reflected in a shorter sleeping time. 

In rats, both age and gender seem to influence strain variation in xenobiotic metabolism. Male rats exhibit about twofold variation between strains in hexobarbital metabolism, whereas female rats may display up to sixfold variation. In either gender the extent of variations depend on age. The ability to metabolize hexobarbital is related to the metabolism of other substrates and the interstrain differences are maintained. 

Chandler, M.H. Scott, S.R. Blouin, R.A. Age-associated stereoselective alterations in hexobarbital metabolism. Clin. Pharmacol. Ther. 1988, 43 (4), 436-441. 

Mendon PJ, Ferguson PW, Watson CF. Effects of Eleutherococcus senticus extracts on hexobarbital metabolism in vivo and in vitro. J Ethnopharmacol 1984 10 235-241. 

We repeated the Vitafiber perfusion experiment using a circulating solution of hexobarbital in human plasma, equilibrated with ambient oxygen (Figure 6). The rate of hexobarbital metabolism was about 50% of that observed with a buffered oxygenated solution. This decreased rate was probably caused by mass transfer limitations secondary to binding of hexobarbital to plasma proteins and by clogging of fiber pores by the plasma proteins. 

An increase in hexobarbital metabolism was observed in mice exposed to corncob bedding that had been sprayed with an ether extract of eastern red cedar (Wade et al. 1968). 

J. R. Robinson and D. W. Nebert, Genetic expression of aryl hydrocarbon hydroxylase induction Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism. Mol. Pharmacol. 10, 484-493 (1974). 

Most species differences in drug metabolism, however, result from differences in the rates of enzymatic convosions. For example, a dose of 50 mg/kg of hexo-barbital produces anaesthesia in man or dog for over S hr but 100 mg/kg produces anaesthesia for 90 min in rats, for 49 min in rabbits and for only 12 min in mice. At the time of recovery from anaesthesia, the several animal spedes have remarkably similar brain barbiturate levels. Thus, the duration of action of hexo-barbital in several species is generally proportional to its biologic half life and inversely proportional to the rate of hexobarbital metabolism by enzymes in hepatic microsomes. 

Table 11. Sex Differences in Hexobarbital Sleeping Time AND Hexobarbital Metabolism by Rat-liver Microsomes...

Species differences in the rate of metabolism of hexobarbital in vitro correlate with the plasma half-life and duration of action in vivo as shown in Table 5.10. This data show that the marked differences in enzyme activity between species is the major determinant of the biological activity in this case. 

Table 5.10 Species Differences in the Duraction of Action and Metabolism of Hexobarbital (Dose of Barbiturate 100 mg kg-1 50 mg kg-1 in Dogs)...

The carcinogenicity of af la toxin is reduced by protein deficiency, presumably because of reduced metabolic activation to the epoxide intermediate, which may be the ultimate carcinogen, which binds to DNA (Fig. 5.14). A deficiency in dietary fatty acids also decreases the activity of the microsomal enzymes. Thus, ethylmorphine, hexobarbital, and aniline metabolism are decreased, possibly because lipid is required for cytochromes P-450. Thus, a deficiency of essential fatty acids leads to a decline in both cytochromes P-450 levels and activity in vivo. 

When the parent compound is responsible for the pharmacological or toxicological effect, reduced metabolic activity may lead to prolonged and exaggerated responses. For example, in mice there is very little oxidation of the side chain of hexobarbital, and the sleeping time is... 

Table 5.20 Effect of Age on Metabolism and Duration of Action of Hexobarbital...

Table 5.27 Effect of the Enzyme Inhibitor Triacetyloleandomycin on Metabolism of Hexobarbital...

Many differences in overall toxicity between males and females of various species are known (Table 9.1). Although it is not always known whether metabolism is the only or even the most important factor, such differences may be due to gender-related differences in metabolism. Hexobarbital is metabolized faster by male rats thus female rats have longer sleeping times. Parathion is activated to the cholinesterase inhibitor paraoxon more rapidly in female than in male rats, and thus is more toxic to females. Presumably many of the gender-related differences, as with the developmental differences, are related to quantitative or qualitative differences in the isozymes of the xenobiotic-metabolizing enzymes that exist in multiple forms, but this aspect has not been investigated extensively. 

Adrenal Hormones. Removal of adrenal glands from male rats results in a decrease in the activity of hepatic microsomal enzymes, impairing the metabolism of aminopyrine and hexobarbital, but the same operation in females has no effect on their metabolism. Cortisone or prednisolone restores activity to normal levels. 

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