Fröhlich Margit, Albermann Nadine, Sauer Alexandra, Walter-Sack Ingeborg, Haefeli Walter E, Weiss Johanna
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Biochem Pharmacol. 2004 Dec 15;68(12):2409-16. doi: 10.1016/j.bcp.2004.08.026.
The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical.
药物作用中众所周知的性别差异，部分原因可能是药物代谢酶活性和表达的变化，但也可能是性类固醇对活性药物转运系统（如P-糖蛋白，Pgp）的调节作用，而这方面尚未得到充分研究。由于许多女性使用激素（如口服避孕药），我们研究了不同合成孕激素对Pgp活性的影响。通过钙黄绿素测定法，在两种过表达Pgp的细胞系（L-MDR1、P388/dx细胞）及其相应的亲本细胞系中，体外测定了孕酮、甲羟孕酮、氯地孕酮、环丙孕酮、左炔诺孕酮、炔诺酮、去氧孕烯和诺孕酯对Pgp的抑制作用；通过罗丹明123外排法，在人外周血单核细胞（PBMC）中进行了体内外研究。对于大多数测试的孕激素，使L-MDR1细胞中基线荧光加倍（f2）所需的浓度与强效Pgp抑制剂奎尼丁相似，而左炔诺孕酮和炔诺酮未达到f2。P388/dx细胞中的结果基本证实了我们在L-MDR1细胞中的发现。此外，所有测试孕激素的Pgp抑制活性在PBMC中也得到了体内外验证。几种合成孕激素在体内外对Pgp的强效抑制作用表明，尽管孕激素的血浆浓度通常较低，但这种相互作用可能具有临床相关性。这些结果对于Pgp底物，如蛋白酶抑制剂和化疗药物，可能尤为重要，因为它们的细胞内浓度至关重要。
