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 pentobarbitone 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 action of pentobarbitone (and hexobarbitone) by changing the rate of barbiturate metabolism. In the case of mestranol, this might be a combination of an effect upon basal metabolic rate (enhancing hypothermia) and a direct effect on the liver. An effect upon renal clearance cannot be excluded by these results.