Efflux transport is an important determinant of ethinylestradiol glucuronide and ethinylestradiol sulfate pharmacokinetics.

Abstract

17α-ethinylestradiol (EE) undergoes extensive conjugation to 17α-ethinylestradiol-3-O-glucuronide (EEG) and 17α-ethinylestradiol-3-O-sulfate (EES). Thus, oral contraceptive drug-drug interaction (DDI) studies usually characterize metabolite pharmacokinetics, with changes typically attributed to modulation of metabolism. EE passively diffuses through plasma membranes, but its conjugates are hydrophilic and require active transport. Unlike EE metabolism, EEG and EES transport has not been explored in vivo as a potential mechanism of DDIs. Recent in vitro studies demonstrated that EEG is transported by multidrug resistance-associated protein (MRP) 2 and MRP3 and EES is a breast cancer resistance protein (BCRP) substrate. In the study presented here, pharmacokinetics of EE and conjugates were studied in TR⁻ rats, which lack Mrp2, have marginal hepatic Bcrp expression, and overexpress hepatic Mrp3. EE pharmacokinetics in TR⁻ rats were comparable to wild type; however, EEG and EES systemic exposures were altered markedly. EEG exposure was greatly increased: 20-fold and >100-fold after intravenous and oral EE administration, respectively. In contrast, EES exposure was lower in TR⁻ rats: 65% decreased (intravenously) and 83% decreased (orally). In intestinal and liver perfusions, EE intestinal permeability and metabolism and hepatic clearance were unchanged in TR⁻ rats; however, secretion of EEG into intestinal lumen was halved, EEG was not detected in TR⁻ bile, and EES biliary excretion was 98% decreased. After oral EE administration to Mrp2- and Bcrp-knockout mice, EEG exposure increased 46- and 2-fold, respectively, whereas EES concentrations were decreased modestly. In conclusion, altered efflux transport resulted in major alterations of EEG and EES pharmacokinetics, highlighting transport as a potential site of DDIs with EE conjugates.

• Authors: Maciej J Zamek-Gliszczynski, Jeffrey S Day, Kathleen M Hillgren, Diane L Phillips
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 39 Issue 10 Pg. 1794-800 (Oct 2011) ISSN: 1521-009X [Electronic] United States
• PMID: 21708882 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcg2 protein, rat
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• ethinyl estradiol glucuronide
• estradiol-17 beta-glucuronide
• multidrug resistance-associated protein 3
• ethinylestradiol-3-sulfate
• Ethinyl Estradiol
• Estradiol

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Administration, Oral
• Animals
• Biliary Tract (metabolism)
• Biological Transport
• Cell Membrane (metabolism)
• Estradiol (analogs & derivatives, pharmacokinetics)
• Ethinyl Estradiol (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
• Half-Life
• Intestinal Mucosa (metabolism)
• Liver (metabolism)
• Male
• Membrane Transport Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Rats
• Rats, Wistar