دانلود رایگان مقاله عملکرد ناقل های دارو در بافت سرویکوواژینال

Abstract

P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4) are three efflux transporters that play key roles in the pharmacokinetics of antiretroviral drugs used in the pre-exposure prophylaxis of HIV sexual transmission. In this study, we investigated the expression, regulation, and function of these transporters in cervicovaginal tissues of a mouse model. Expression and regulation were examined using real-time RT-PCR and immunohistochemical staining, in the mouse tissues harvested at estrus and diestrus stages under natural cycling or after hormone synchronization. The three transporters were expressed at moderate to high levels compared to the liver. Transporter proteins were localized in various cell types in different tissue segments. Estrous cycle and exogenous hormone treatment affected transporter mRNA and protein expression, in a tissue- and transporter-dependent manner. Depo-Provera-synchronized mice were dosed vaginally or intraperitoneally with 3H-TFV, with or without MK571 co-administration, to delineate the function of cervicovaginal Mrp4. Co-administration of MK571 significantly increased the concentration of vaginally-administered TFV in endocervix and vagina. MK571 increased the concentration of intraperitoneally-administered TFV in the cervicovaginal lavage and vagina by several fold. Overall, P-gp, Bcrp, and Mrp4 were positively expressed in mouse cervicovaginal tissues, and their expression can be regulated by the estrous cycle or by exogenous hormones. In this model, the Mrp4 transporter impacted TFV distribution in cervicovaginal tissues.

4. Discussion

In this study, we have examined the expression and regulation of P-gp (Abcb1a/1b), Bcrp, and Mrp4 in mouse cervicovaginal and colorectal tissues, under the influence of the mouse estrous cycle and of exogenous hormones. In addition, we have provided proof of concept that cervicovaginal and colorectal Mrp4 could affect TFV tissue absorption/disposition under certain circumstances, and that this effect may be reversed by co-administration of an MRP inhibitor MK571. To our knowledge, this is the first report revealing the effect of menstrual (estrous) cycle and exogenous hormones on the expression of the three transporters in cervicovaginal tissues. In addition, this is the first report of cervicovaginal tissue MRP4 function in an in vivo model.