Interaction of progestins with the human multidrug resistance-associated protein 2 (MRP2).
Progestins are widely used as oral contraceptives and hormone replacement therapy. Recently it has been demonstrated that many progestins are inhibitors of P-glycoprotein, possibly explaining gender differences in drug actions. In vitro evidence suggested that at least norgestimate might also inhibit other transporters like the multidrug resistance-associated protein 2 (MRP2). We therefore investigated whether norgestimate, desogestrel, medroxyprogesterone acetate, norethisterone, progesterone, cyproterone acetate, chlormadinone acetate, and levonorgestrel inhibit MRP2 in vitro using confocal laser scanning microscopy and 5-chloromethylfluorescein diacetate as a prodrug of the fluorescent 5-chloromethylfluorescein (CMF), which is actively transported by MRP2 as glutathione conjugate. Of the progestins tested, only norgestimate (50 microM) and progesterone (100 microM) significantly increased intracellular CMF fluorescence by 62% and 53%, respectively. In conclusion, the progestins norgestimate and progesterone significantly inhibit the transport activity of MRP2 in vitro.
Lindenmaier
Heike
H
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Becker
Melanie
M
Haefeli
Walter Emil
WE
Weiss
Johanna
J
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D006801:Humans; D018613:Microscopy, Confocal; D009644:Norgestrel / Q000031:analogs & derivatives / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014162:Transfection; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D003280:Contraceptives, Oral, Synthetic; D005452:Fluoresceins; D009644:Norgestrel; D011374:Progesterone; D011372:Progestins; D011422:Propionates; D011804:Quinolines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C069306:5-chloromethylfluorescein; C059141:verlukast; C017576:norgestimate