ArticleInternational journal of pharmaceutics2016
Circumvention of P-gp and MRP2 mediated efflux of lopinavir by a histidine based dipeptide prodrug.
Article in International journal of pharmaceutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
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Who cites it
6 citing papers in PubMed, 17 citations in OpenAlex.
- Effects of Dietary Crude Protein Level on Growth Performance, Immune Function, and Serum Metabolic Profile in Weaned Piglets.Animals : an open access journal from MDPI · 2026Article
- Walnut Peptide KG-7 Alleviates Scopolamine-Induced Memory Deficits and Enhances Paracellular Transport via Tight Junction Modulation in a Mouse Model.Foods (Basel, Switzerland) · 2026Article
- Structure-activity analysis of imino-pyrimidinone-fused pyrrolidines aids the development of dual plasmepsin V and plasmepsin X inhibitors.The FEBS journal · 2025Article
- Prodrug Approach as a Strategy to Enhance Drug Permeability.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability: In Vitro and In Silico Preliminary Study.European journal of drug metabolism and pharmacokinetics · 2024Article
- Transporter-Mediated Drug Delivery.Molecules (Basel, Switzerland) · 2023Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
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 (1)H 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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Registered trials
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