In Silico and in Vitro Screening for P-Glycoprotein Interaction with Tenofovir, Darunavir, and Dapivirine: An Antiretroviral Drug Combination for Topical Prevention of Colorectal HIV Transmission

• DOI: 10.1021/acs.molpharmaceut.7b00133
• Publication Date: 2017-06-25T17:09:13Z
• Authors: Magda Swedrowska; Shirin Jamshidi; Abhinav Kumar; Charles Kelly; Khondaker Miraz R...; Ben Forbes
• Keywords: Darunavir; Reverse-transcriptase inhibitor; P-glycoprotein

The aim of the study was to use in silico and vitro techniques evaluate whether a triple formulation antiretroviral drugs (tenofovir, darunavir, dapivirine) interacted with P-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions colorectal mucosa. Potential drug P-gp were screened initially using molecular docking, followed by dynamics simulations analyze identified drug-transporter interaction more mechanistically. transport tenofovir, dapivirine investigated Caco-2 cell models tissue, their apparent permeability coefficient (Papp), efflux ratio (ER), effect transporter inhibitors evaluated. In silico, darunavir showed strong affinity for similar free energy binding; exhibiting ΔGPB value -38.24 kcal/mol, -36.84 kcal/mol. rank order compounds tenofovir < dapivirine. Papp monolayers 0.10 ± 0.02 × 10-6 cm/s, ER = 1. For dapivirine, 32.2 3.7 but 1.3 lower than anticipated based on findings. Neither nor influenced inhibitors. absorptive (Papp 6.4 0.9 cm/s) concentration dependent 6.3, which reduced verapamil 1.2. Administration combination did not alter compared administration as single agents. conclusion, modeling, culture, tissue-based assays that does interact is poorly permeable, consistent paracellular mechanism. modeling predicted substrates, only P-gp-dependent biological models, illustrating requires experimental validation. When administered combination, disposition proposed triple-therapy mucosa will depend distinctly different permeability, interdependent.