Received for publication April 25, 2005.
Revised July 22, 2005.
Accepted for publication July 22, 2005.

Interaction of progestins with the human multidrug resistance-associated protein 2 (MRP2)

Abstract

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-chloromethyl-fluorescein diacetate (CMFDA) 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.

Key words: ABC transporters, clinical pharmacology, drug distribution, drug efflux, drug interactions, drug-drug interactions, inhibition, MRP, multi-drug resistance, p-glycoprotein