Differential Effects of Oral Contraceptive Steroids on the Metabolism of Benzodiazepines

The effects of oral contraceptives (OCs) on the disposition and elimination of lorazepam oxazepam and chlordiazepoxide were examined. Lorazepam and oxazepam are metabolized via glucuronidation while chlordiazepoxide is metabolized by oxidation in the liver. The disposition and elimination of lorazepam oxazepam and chlordiazepoxide were studied in females not taking OCs and females who were (norethindrone acetate 1mg; ethinyl estradiol 50 mcg) for 6 months or longer. The t1/2 (beta) for lorazepam was significantly reduced in women taking OCs (6.0 +or- 3.1 vs. 14.0 +or- 6.2 hours) (p<0.005) as compared to controls and the t1/2 (beta) for oxazepam was reduced in women taking OCs (7.71 +or- 3.23 vs. 12.09 +or- 5.08 hours) as compared to controls but did not reach statistical significance. The plasma clearance of both lorazepam and oxazepam was significantly increased in women taking OCs (288.9 +or- 165.9 vs. 77.5 +or- 3.29 ml/minute) (p<0.01) and 251.2 +or- 106.9 vs. 97.86 +or- 69.4 ml/minute) (p<0.01) respectively as compared to controls. The volumes of distribution of lorazepam and oxazepam were significantly increased in women taking OCs (p<0.05) while plasma binding of these drugs was similar in both groups. In contrast the t1/2 (beta) of chlordiazepoxide was significantly prolonged (20.58 +or- 8.08 vs. 11.63 +or- 5.91 hours) (p<0.05) and the plasma clearance was reduced (13.41 +or- 4.69 vs. 33.22 +or- 12.37 ml/minute) (p<0.05) in the OCs group as compared to controls. The volumes of distribution of chlordiazepoxide were similar in both groups and the plasma binding of chlordiazepoxide tended to be lowe in the OC group but did reach statistical significance. We conclude that OCs exert a differential effect on the elimination of benzodiazepines whereby oxidation of chlordiazepoxide is impaired while the glucuronidation of lorazepam and oxazepam is enhanced by OCs. (authors)