No abstract

Two low-dose oral contraceptives, both containing the same dose of ethinyl estradiol (EE₂) but different progestins (gestodene and desogestrel, respectively), were compared with respect to the relative bioavailability of EE₂. The study was conducted with 31 women as an open intraindividual comparison with the ingestion of both preparations for 3 months, respectively. On days 1,10 and 21 of the 1 st, 3rd and 6th cycle, blood was sampled at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 h following administration. The concentrations of EE₂ were determined in the serum samples of each individual and the area under the serum concentration versus time curves, AUC (0–4 h) and AUC (0–24 h), were calculated. Corresponding parameters obtained on days 1,10 and 21 of the 3rd and 6th month of treatment were compared on a statistical basis, and no differences were found. This result was in concordance with a previously performed study, where both formulations were administered to 18 women in a single-dose cross-over design. However, the results of the previous and the present study are at variance with the result of one other study, reporting higher EE₂ levels in the serum of women taking the gestodene-containing formulation as compared to those taking the desogestrel-containing formulation.

Summary. Male rats were treated with 5 or 20 mg cyproterone acetate/kg/day or 20 mg cyproterone/rat/day for 1, 2, 3, 4 or 5 weeks. There was some reduction in fertility with both compounds, the maximum effect occurring after 5

1. D0870, an azole antifungal agent, produced dose-related increases in total cytochrome P450 and aldrin epoxidase when administered as 14 daily oral doses (0, 0.5, 2.5 and 12.5 mg/kg/day) to the male rat. Administered as single doses, D0870 increased pentobarbitone-sleeping time in a dose-related manner. 2. In human hepatic microsomal incubations, D0870 produced pronounced inhibition of CYP2C9 (tolbutamide hydroxylase) and, to a lesser degree, CYP3A4 (testosterone 6beta-hydroxylase), but had more limited effects on CYP1A2, 2C19 and 2D6 activity. In comparison with ketoconazole, itraconazole and fluconazole, D0870 was the most potent inhibitor of CYP2C9 activity. It is predicted that D0870 may inhibit the in vivo clearance of CYP2C9 substrates by approximately 58%, thereby increasing their steady-state concentrations by 2.4 times, which would be of clinical significance for some compounds. 3. During incubation of [14C]-D0870 with cultured human hepatocytes for up to 72 h, two discrete metabolites (A and B) were formed. Formation of metabolite A was abolished by both quinidine and ketoconazole and is probably CYP3A4-mediated, whereas generation of metabolite B did not appear to be dependent on cytochrome P450. 4. D0870 has potential to produce both induction and inhibition of cytochrome P450 enzymes in man.

Esterase activity in leukocytes demonstrated by the use of naphthol AS-D chloroacetate substrate.