The effects of oestrogens and progestins on the response of mice to barbiturates

Abstract

1. Mestranol (oestrogen) prolonged, whilst lynestrenol (progestin) reduced, the duration of pentobarbitone and hexobarbitone sleep in mice, whilst the effects of barbitone were not altered. 2. The effects of these steroids on pentobapbitone sleep were dose-related, did not show tachyphylaxis, and produced optimal effects after only 4 days pretreatment.3. The effects of lynestrenol were abolished by SKF 525A, whilst those of mestranol were markedly potentiated, suggesting a different mechanism and/or locus of action for mestranol and SKF 525A. 4. Examination of plasma levels of pentobarbitone in mice pretreated with mestranol, lynestrenol or SKF 525A showed that lynestrenol increased whilst mestranol and SKF 525A reduced the rate of clearance of barbiturate from the plasma. 5. The effects of lynestrenol disappeared when pentobarbitone was prevented from inducing hypothermia, whilst some significant prolongation of pentobarbitone sleep persisted in mestranol treated mice. This suggested that the ability to potentiate hypothermia was not the sole mechanism by which the effects of pentobarbitone were enhanced by mestranol. 6. It is concluded these steroids alter the duration of aiction of pentobarbitone (and hexobarbitone) by changing the rate of barbiturate metalbolism. In the case of mestranol, this might be a combination of an effect upon basal metalbolic rate (enhancing hypothermia) and a direct effect on the liver. An effect upon renal clearance cannot be excluded by these results.

Effects of Contraceptive Agents on Drug Metabolism in Various Animal Species

“…This effect is probably produced by the progestogenic compounds alone, because, at least for one of the combined treatments tested in two animal species, the oestrogen alone is almost devoid of activity. These results agree with those previously obtained by our laboratory (Jori et al, 1969) and by other authors (Blackham & Spencer, 1969), concerning the effect of oestrogens on drug metabolism in vivo and in vitro. However a potentiating effect of the oestrogens on the activity of the progestogens cannot be excluded at least for some substrates.…”

“…Similar inducing effects were obtained by Juchau & Fouts (1966) and Riimke & Noordhoek (1969). An increase in the metabolism of barbiturates after oestrogen and progestogen contraceptive treatment was also found in mice (Blackham & Spencer, 1969;Garg & Ahmad, 1974).…”

Hormonal Regulation of Hepatic Drug-Metabolizing Enzyme Activity During Adolescence

“…(43) Estrogens, in contrast, have been shown to decrease hepatic microsomal activity and drug clearance in rodents via a reduction in the amount of microsomal DME protein. (44, 45) The reported effects of progesterones on DME activity are variable and inconsistent with some investigations reporting an inhibitory effect (46) and others reporting an inductive effect. (44)…”

“…(44, 45) The reported effects of progesterones on DME activity are variable and inconsistent with some investigations reporting an inhibitory effect (46) and others reporting an inductive effect. (44)…”

Influence of menstrual cycle on antipyrine pharmacokinetics in healthy Indian female volunteers.

“…Stilboestrol, administered to normal men, impaired the metabolism of pethidine (Crawford & Rudofsky, 1966). Blackham & Spencer (1969) have reported that oestrogens prolonged while progestagens reduced drug metabolism but this effect was dose related. Oram et al (1982) observed that oral contraceptive administration abolished the increase in the rate of methaqualone metabolism during the mid-cycle.…”