Abstract
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 μM) and progesterone (100 μM) 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.005314.
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ABBREVIATIONS: MRP, human multidrug resistance-associated protein; CMF, 5-chloromethylfluorescein; CMFDA, 5-chloromethylfluorescein diacetate; MF-SG, methylfluorescein-sulfoglutathione; P-gp, P-glycoprotein; ANOVA, analysis of variance.
- Received April 25, 2005.
- Accepted July 22, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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