Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women

Alison Edelman, Myrna Munar, Miriam R. Elman, Dennis Koop, Ganesh Cherala

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

AIM(S) While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. METHODS Thirty-four, obese (body mass index, BMI > 30kgm-2) women of reproductive age (18-35years old) were placed on a COC pill containing 20μg ethinylestradiol/100μg levonorgestrel for 21days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. RESULTS Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3lh-1vs. 53.9lh-1, P <0.05). A median decrease of 5.6lh-1 (95% CI -4.1, 13.3lh-1) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. CONCLUSIONS Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.

Original languageEnglish (US)
Pages (from-to)510-514
Number of pages5
JournalBritish Journal of Clinical Pharmacology
Volume74
Issue number3
DOIs
StatePublished - Sep 2012

Fingerprint

Contraceptives, Oral, Combined
Levonorgestrel
Ethinyl Estradiol
Cytochromes
Cytochrome P-450 CYP3A
Midazolam
Obesity
Pharmacokinetics
Contraception Behavior
Menstruation
Tandem Mass Spectrometry
Drug Interactions
Liquid Chromatography
Pharmaceutical Preparations
Body Mass Index

Keywords

  • Combined oral contraceptives
  • Cytochrome P4503A
  • Ethinylestradiol
  • Levonorgestrel
  • Obesity
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women. / Edelman, Alison; Munar, Myrna; Elman, Miriam R.; Koop, Dennis; Cherala, Ganesh.

In: British Journal of Clinical Pharmacology, Vol. 74, No. 3, 09.2012, p. 510-514.

Research output: Contribution to journalArticle

@article{9ea14e72b1344cfdbbf4f00a4db277b0,
title = "Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women",
abstract = "AIM(S) While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. METHODS Thirty-four, obese (body mass index, BMI > 30kgm-2) women of reproductive age (18-35years old) were placed on a COC pill containing 20μg ethinylestradiol/100μg levonorgestrel for 21days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. RESULTS Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3lh-1vs. 53.9lh-1, P <0.05). A median decrease of 5.6lh-1 (95{\%} CI -4.1, 13.3lh-1) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. CONCLUSIONS Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.",
keywords = "Combined oral contraceptives, Cytochrome P4503A, Ethinylestradiol, Levonorgestrel, Obesity, Pharmacokinetics",
author = "Alison Edelman and Myrna Munar and Elman, {Miriam R.} and Dennis Koop and Ganesh Cherala",
year = "2012",
month = "9",
doi = "10.1111/j.1365-2125.2012.04209.x",
language = "English (US)",
volume = "74",
pages = "510--514",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women

AU - Edelman, Alison

AU - Munar, Myrna

AU - Elman, Miriam R.

AU - Koop, Dennis

AU - Cherala, Ganesh

PY - 2012/9

Y1 - 2012/9

N2 - AIM(S) While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. METHODS Thirty-four, obese (body mass index, BMI > 30kgm-2) women of reproductive age (18-35years old) were placed on a COC pill containing 20μg ethinylestradiol/100μg levonorgestrel for 21days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. RESULTS Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3lh-1vs. 53.9lh-1, P <0.05). A median decrease of 5.6lh-1 (95% CI -4.1, 13.3lh-1) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. CONCLUSIONS Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.

AB - AIM(S) While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. METHODS Thirty-four, obese (body mass index, BMI > 30kgm-2) women of reproductive age (18-35years old) were placed on a COC pill containing 20μg ethinylestradiol/100μg levonorgestrel for 21days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. RESULTS Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3lh-1vs. 53.9lh-1, P <0.05). A median decrease of 5.6lh-1 (95% CI -4.1, 13.3lh-1) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. CONCLUSIONS Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.

KW - Combined oral contraceptives

KW - Cytochrome P4503A

KW - Ethinylestradiol

KW - Levonorgestrel

KW - Obesity

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=84859527366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859527366&partnerID=8YFLogxK

U2 - 10.1111/j.1365-2125.2012.04209.x

DO - 10.1111/j.1365-2125.2012.04209.x

M3 - Article

VL - 74

SP - 510

EP - 514

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 3

ER -