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  • Title: Impairment of diazepam metabolism by low-dose estrogen-containing oral-contraceptive steroids.
    Author: Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, Shader RI.
    Journal: N Engl J Med; 1982 Apr 01; 306(13):791-2. PubMed ID: 7062953.
    Abstract:
    The longterm use of low-dose estrogen containing oral contraceptives (OCs) and its impairment of diazepam clearance is reported. 8 healthy women, ranging in age from 52 to 72 years, participated in the study. All of the women had been taking low-dose estrogen containing OCs for more than 3 months. 1 of the subjects was a cigarette smoker. 8 healthy controls (all nonsmokers) who were not using OCs also participated. They ranged in age from 27-31 years. Diazepam (10 mg) was given by intravenous infusion over 15-30 seconds. Venous blood samples were drawn into heparinized tubes before the infusion, at the end of the infusion, at 5, 15, 30, and 45 minutes, at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours, and daily for 7 days after the infusion. Plasma concentrations of diazepam after intravenous infusion were analyzed by weighted iterative nonlinear least-squares regression techniques. The volume of distribution of diazepam was not significantly different between the groups, but the apparent elimination half-life of diazepam was significantly longer and the total metabolic clearance significantly less in the OC users than in the control group. The differences were not confounded by variations in protein binding. The mean diazepam free fraction was identical in the 2 groups. The clinical result of the decrease in diazepam clearance reported here would be increased steady-state plasma diazepam concentration after longterm use at a given daily dose, with the potential for increasing the clinical effects of diazepam in this population.
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