PT  - JOURNAL ARTICLE
AU  - Maciej J Zamek-Gliszczynski
AU  - Jeffrey S Day
AU  - Kathleen M Hillgren
AU  - Diane L. Phillips
TI  - Efflux transport is an important determinant of ethinylestradiol glucuronide and ethinylestradiol sulfate pharmacokinetics
AID  - 10.1124/dmd.111.040162
DP  - 2011 Jun 27
TA  - Drug Metabolism and Disposition
PG  - dmd.111.040162
4099  - http://dmd.aspetjournals.org/content/early/2011/06/27/dmd.111.040162.short
4100  - http://dmd.aspetjournals.org/content/early/2011/06/27/dmd.111.040162.full
AB  - Ethinylestradiol (EE) undergoes extensive conjugation to EE-3-O-glucuronide (EEG) and EE-3-O-sulfate (EES). Thus oral contraceptive 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 MRP2 and MRP3 and EES is a BCRP substrate. In the present study, 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 following intravenous and oral EE administration, respectively. In contrast, EES exposure was lower in TR- rats: 65% decreased (intravenous) and 83% decreased (oral). In intestinal and liver perfusions, EE intestinal permeability and metabolism, as well as 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. Following oral EE administration to Mrp2- and Bcrp-knockout mice, EEG exposure increased 46 and 2 fold, respectively, while 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.