The effect of ethinyloestradiol and levonorgestrel on the CYP2C19-mediated metabolism of omeprazole in healthy female subjects

Abstract

Aims: To study the effect of an oral contraceptive (OC) formulation containing ethinyloestradiol and levonorgestrel (LNG) (combination OC) or LNG alone on the CYP2C19-mediated hydroxylation of omeprazole in healthy females.

Methods: This was an open crossover study with three phases. In phase one, 10 healthy females received a single 40-mg dose of omeprazole. Thereafter the subjects received in a random order either 40 micro g ethinyloestradiol and 75 micro g LNG or 60 micro g LNG alone once daily for 10 days. On day 10, 1 h after the last OC dose, subjects received a single 40-mg oral dose of omeprazole. The plasma concentrations of omeprazole, 5'-hydroxyomeprazole and omeprazole sulphone were determined for up to 8 h.

Results: The use of combination OC increased the area under the curve (AUC) of omeprazole by 38% [95% confidence interval (CI) - 3.8, 80; P = 0.040] and caused a 48% increase (95% CI 28, 68) in the AUC ratio of omeprazole/5-hydroxyomeprazole. LNG alone did not effect the 5'-hydroxylation of omeprazole. Neither of the OC preparations seemed to have an inhibitory effect on the formation of omeprazole sulphone by CYP3A4.

Conclusions: Oral contraceptives containing ethinyloestradiol but not those containing only LNG decrease CYP2C19 activity.

Figure 1

The metabolism of omeprazole and its major metabolites shown schematically.

Figure 2

The mean concentration vs. time profiles for (a) omeprazole, (b) OH-omeprazole and (c) omeprazole sulphone in 10 healthy subjects after a single 40-mg oral dose of omeprazole, without pretreatment (♦) and following pretreatment with the combination oral contraceptive (▪) or levonorgestrel alone for 10 days (□). The error bars have been omitted for clarity.