An Ethinyl Estradiol-Levonorgestrel Containing Oral Contraceptive Does Not Alter Cytochrome P4502C9 In Vivo Activity

Abstract

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C 24 ) was measured using liquid chromatography-mass spectrometry. The natural logarithm of tolbutamide C 24 , a metric for CYP2C9 phenotype, was found to be equivalent (within 80%-125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to coadminister levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs.

Atogepant Has No Clinically Relevant Effects on the Pharmacokinetics of an Ethinyl Estradiol/Levonorgestrel Oral Contraceptive in Healthy Female Participants

“…25,26 The primary metabolic pathways for LNG are oxidation, reduction, and direct sulfation. 21,26,29 Atogepant does not induce or inhibit CYP2D6, CYP3A4, or P-glycoprotein at clinically relevant concentrations, and therefore, drug interactions through CYP450s or UGT1A1 or P-glycoprotein inhibition are unlikely.…”

Pharmacokinetic drug–drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel‐ethinyl estradiol in healthy subjects

“…Levonorgestrel in combination with ethinyl estradiol is a commonly used COC. 29 In the current study, levonorgestrel and ethinyl estradiol were given as single dose because changes in pharmacokinetics of levonorgestrel and ethinyl estradiol at steady state after multiple dose administration can be estimated based on any observed changes in pharmacokinetics of single dose. From the known pharmacokinetic properties of LCZ696, levonorgestrel, and ethinyl estradiol, no pharmacokinetic interaction was anticipated.…”

PharmVar GeneFocus: CYP2C9

“…Data obtained in liver microsomes with tolbutamide as substrate 51,52 and from phenotyping studies with losartan and tolbutamide as substrates 53,54 did not reveal differences in activity between males and females, with the exception of one study that found slower metabolism of losartan in females compared with males 53 . It has also been reported that females taking oral contraceptives show impairment of losartan metabolism, 55 although this observation was not replicated using tolbutamide as substrate 56 . However, considering that estrogens upregulate CYP2C9 expression via the estrogen receptor, 57 studies on sex differences should consider this possible confounder.…”

“…53 It has also been reported that females taking oral contraceptives show impairment of losartan metabolism, 55 although this observation was not replicated using tolbutamide as substrate. 56 However, considering that estrogens upregulate CYP2C9 expression via the estrogen receptor, 57 studies on sex differences should consider this possible confounder.…”