Effect of oral contraceptives on drug metabolism in humans and rats.

The chronic use of steroidal oral contraceptive (OC) agents on drug metabolism in humans and rats was studied. Rats received daily doses of norethynodrel 200 mcg plus mestranol 4 mcg for 10 days and again for 6 weeks in order to study the demethylation of ethylmorphine in rat liver preparations. The rates of plasma disappearance of antipyrine (AP) and phenylbutazone (PBz) were used as the test for OC metabolic effects in human subjects. In Phase 1 1 gm AP was given orally on Day 1; 20 ml blood samples were collected for 24 hours. On Day 3 300 mg PBz was given orally and 20 ml samples collected for 96 hours. Plasma AP levels were determined by the method of Brodie et al. and PBz by the method of Burns et al. Phase 2 occurred after 3 months of OC (Enovid; 5 mg noreth ynodrel plus .075 mg mestranol) use and drug half-lives were again deter mined. In addition radioactive norethyndrel (50-75 mc curies) was given 2 days before AP administration. 20 ml blood samples were drawn for 48 hours and urine collected at 6-hourly intervals for 48 hours. Phase 3 occurred 2 months after the end of Phase 2. Subjects were placed on 300 mg/day PBz for 30 days in addition to OC therapy. Determinations were repeated. The metabolism of norethynodrel was studied by determining the level of the 3beta-hydroxy metabolite the 3alpha-hydroxy metabolite norethindrone and the polar polyhydroxy metabolites both free and co njugated in the plasma. The metabolism of norethynodrel was also tested in women who had experienced thrombophlebitic-thromboembolic episodes on pill therapy by the above procedure for labeled norethynodrel. Results indicate that women with OC-related thromboembolic-thrombophlebitic disease metabolize norethynodrel similarly to controls. Chronic OC therapy in humans causes an increased rate of glucuronidation of norethynodrel metabolites indicating norethynodrel was inducing its own metabolism. Chronic OC therapy caused inhibition of AP metabolism in 5 of 8 women in the study. PBz metabolism remained unaffected. 2 women with inhibition of AP and PBz metabolism experienced thromboembolic-thrombophlebitic disease. Results indicate that OC thera py blocks induction of some xenobiotics. Studies with rat liver preparations showed acute inhibition with the addition of norethynodrel in vitro and stimulation of ethylmorphine demethylase activity after chronic administration of a norethynodrel-mestranol mixture.