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. MethodsThis 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 m g ethinyloestradiol and 75 m g LNG or 60 m 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.

IS 17α-Ethinyl ESTRADIOL AN INHIBITOR OF CYTOCHROME P450 2C19?

“…Because the hydroxylation of omeprazole is widely accepted as an index of CYP2C19 activity (Chang et al, 1995;Lasker et al, 1998;Abelo et al, 2000;Kita et al, 2001), the authors concluded that OC preparations containing EE decrease CYP2C19 activity. The observations of Palovaara et al (2003) confirm the findings of Laine et al (2000), who also reported an increase (ϳ100%) in the omeprazole to 5-hydroxy omeprazole ratio in plasma. In the same study, the ratio of (S)-mephenytoin to (R)-mephenytoin in urine (S/R ratio) increased from 0.11 to 0.28, and the effect was similar to that observed with subjects genotyped CYP2C19*1/*2 (versus CYP2C19*1/*1).…”

“…For example, Palovaara et al (2003) evaluated the effect of two OC formulations on the hydroxylation of omeprazole. One formulation contained EE (40 g) and LNG (60 g), whereas the second contained LNG (60 g) and was devoid of EE.…”

Molecular and Pharmacological Properties of a Potent and Selective Novel Nonsteroidal Progesterone Receptor Agonist Tanaproget

“…TNPR does not have the potential to induce CYP3A4, whereas 3-ketodesogestrel, a metabolite of desogestrel, has the capacity to induce this isozyme. TNPR does not inhibit any of the major P450 enzymes (data not shown), whereas steroidal progestins have the potential to inhibit CYP2C19, an isozyme that is responsible for the metabolism of proton pump inhibitors such as omeprazole (36). These characteristics of TNPR clearly demonstrate that, unlike other steroidal progestins, the efficacy of TNPR will likely not be affected by any concomitant drugs and that TNPR should not interfere with the efficacy of other drugs.…”

CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking

“…The oral contraceptives may contain progestin with or without ethinyl oestradiol and it is not known whether it is the oestrogen or the progestin component that inhibits drug metabolism [10]. The inhibition of CYP2C19 activity by OC seems to be due to the ethinyloestradiol component of OCs [27,28]. The mechanism behind this effect) is unknown but has been suggested to be interaction at the active site between the hormones and the CYP2C19 substrates.…”