کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2500768 | 1557307 | 2016 | 12 صفحه PDF | دانلود رایگان |
PurposeThis study was aimed to develop a novel Histidine-Leucine-Lopinavir (His-Leu-LPV) dipeptide prodrug and evaluate its potential for circumvention of P-gp and MRP2-mediated efflux of lopinavir (LPV) indicated for HIV-1 infection.MethodsHis-Leu-LPV was synthesized following esterification of hydroxyl group of LPV and was identified by 1H NMR and LCMS/MS techniques. Aqueous solubility, stability and cell cytotoxicity of prodrug was determined. Uptake and permeability studies were carried out using P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cell lines. To further delineate prodrug uptake, prodrug interaction with influx transporters (PepT1 and PHT1) was determined. Enzymatic hydrolysis and reconversion of His-Leu-LPV to LPV was examined using Caco-2 cell homogenates.ResultsAqueous solubility generated by the prodrug was markedly higher relative to unmodified LPV. Importantly, His-Leu-LPV displayed significantly lower affinity towards P-gp and MRP2 as evident from higher uptake and transport rates. [3H]-GlySar and [3H]-l-His uptake receded to approximately 30% in the presence of His-Leu-LPV supporting the PepT1/PHT1 mediated uptake process. A steady regeneration of LPV and Leu-LPV in Caco-2 cell homogenates indicated His-Leu-LPV undergoes both esterase and peptidase-mediated hydrolysis.ConclusionHistidine based dipeptide prodrug approach can be an alternative strategy to improve LPV absorption across poorly permeable intestinal barrier.
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Journal: International Journal of Pharmaceutics - Volume 512, Issue 1, 15 October 2016, Pages 49–60