Transport and Permeation Properties of Dapivirine: Understanding Potential Drug-Drug Interactions.
Transport and Permeation Properties of Dapivirine: Understanding Potential Drug-Drug Interactions.
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DOI：
10.3390/pharmaceutics14091948
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发表时间：
2022-09-14
期刊：
影响因子：
5.4
通讯作者：
Rohan LC
中科院分区：
文献类型：
--
作者：
Zheng R;Valicherla GR;Zhang J;Nuttall J;Silvera P;Marshall LJ;Empey PE;Rohan LC
达匹韦林（DPV）阴道环是由非营利组织国际杀微生物剂合作组织（IPM）开发的，用于降低艾滋病毒感染的风险。一项临床研究（IPM 028）显示，同时使用DPV环和咪康唑（MIC）改变了DPV的药代动力学特征。在这项工作中，我们调查是否DPV运输和渗透所观察到的DPV-MIC相互作用的贡献。我们的研究使用囊泡和细胞系统评价了DPV与在人类女性生殖道中高度表达的几种转运蛋白（包括MRP 1、MRP 4、P-gp、BCRP和ENT 1）之间的相互作用。我们还评估了DPV/MIC对细胞紧密连接的影响，通过监测跨上皮电阻与Ussing室。最后，我们评估了MIC对DPV穿过人宫颈组织的渗透性的影响。我们的研究结果表明，DPV不是MRP 1、MRP 4、P-gp、BCRP或ENT 1转运蛋白的底物。此外，DPV不抑制这些转运蛋白的活性。DPV、MIC及其组合也不破坏细胞紧密连接。MIC不影响DPV组织渗透性，但显著降低DPV组织水平。因此，我们的研究结果表明，DPV-MIC相互作用不是由于这五个转运蛋白，改变紧密连接的完整性，或改变组织渗透性。
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.
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DOI：
10.1097/qai.0000000000000897
发表时间：
2016-04-15
影响因子：
3.6
作者：
Bunge, Katherine E.;Dezzutti, Charlene S.;Hillier, Sharon L.
通讯作者：
Hillier, Sharon L.
影响因子：
2.1
作者：
Fan, Shangrong;Liu, Xiaopingliu;Liang, Yiheng
通讯作者：
Liang, Yiheng
影响因子：
3.7
作者：
Hendrix CW;Chen BA;Guddera V;Hoesley C;Justman J;Nakabiito C;Salata R;Soto-Torres L;Patterson K;Minnis AM;Gandham S;Gomez K;Richardson BA;Bumpus NN
通讯作者：
Bumpus NN
研究药物代谢酶在dapivirine和Miconazole的药物相互作用中的贡献。
影响因子：
5.4
作者：
Valicherla GR;Graebing P;Zhang J;Zheng R;Nuttall J;Silvera P;Rohan LC
通讯作者：
Rohan LC
影响因子：
3.7
作者：
Hijazi K;Cuppone AM;Smith K;Stincarelli MA;Ekeruche-Makinde J;De Falco G;Hold GL;Shattock R;Kelly CG;Pozzi G;Iannelli F
通讯作者：
Iannelli F