Zheng Ruohui, Valicherla Guru R, Zhang Junmei, Nuttall Jeremy, Silvera Peter, Marshall Leslie J, Empey Philip E, Rohan Lisa C
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Pharmaceutics. 2022 Sep 14;14(9):1948. doi: 10.3390/pharmaceutics14091948.
The dapivirine (DPV) vaginal ring was developed by the nonprofit International Partnership for Microbicides (IPM) for reducing the risk of HIV infection. A clinical study (IPM 028) showed that concomitant use of the DPV ring and miconazole (MIC) altered DPV pharmacokinetic profile. In this work, we investigated whether or not DPV transport and permeation contributed to the observed DPV-MIC interaction. Our study evaluated the interaction between DPV and several transporters that are highly expressed in the human female reproductive tract, including MRP1, MRP4, P-gp, BCRP, and ENT1, using vesicular and cellular systems. We also evaluated the impact of DPV/MIC on cellular tight junctions by monitoring transepithelial electrical resistance with the Ussing chamber. Lastly, we evaluated the effect of MIC on DPV permeability across human cervical tissue. Our findings showed that DPV was not a substrate of MRP1, MRP4, P-gp, BCRP, or ENT1 transporters. Additionally, DPV did not inhibit the activity of these transporters. DPV, MIC, and their combination also did not disrupt cellular tight junctions. MIC did not affect DPV tissue permeability but significantly reduced DPV tissue levels. Therefore, our results suggest that the DPV-MIC interaction is not due to these five transporters, altered tight junction integrity, or altered tissue permeability.
达匹韦林（DPV）阴道环由非营利性组织国际杀微生物剂合作组织（IPM）研发，用于降低HIV感染风险。一项临床研究（IPM 028）表明，DPV环与咪康唑（MIC）同时使用会改变DPV的药代动力学特征。在这项研究中，我们调查了DPV的转运和渗透是否导致了所观察到的DPV-MIC相互作用。我们的研究使用囊泡和细胞系统评估了DPV与几种在人类女性生殖道中高表达的转运蛋白之间的相互作用，这些转运蛋白包括多药耐药相关蛋白1（MRP1）、多药耐药相关蛋白4（MRP4）、P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）和等效核苷转运体1（ENT1）。我们还通过使用尤斯灌流小室监测跨上皮电阻，评估了DPV/MIC对细胞紧密连接的影响。最后，我们评估了MIC对DPV跨人宫颈组织渗透性的影响。我们的研究结果表明，DPV不是MRP1、MRP4、P-gp、BCRP或ENT1转运蛋白的底物。此外，DPV不会抑制这些转运蛋白的活性。DPV、MIC及其组合也不会破坏细胞紧密连接。MIC不影响DPV的组织渗透性，但会显著降低DPV的组织水平。因此，我们的结果表明，DPV-MIC相互作用不是由于这五种转运蛋白、紧密连接完整性改变或组织渗透性改变所致。
