ArticleInternational journal of pharmaceutics2008
Peptide prodrugs: improved oral absorption of lopinavir, a HIV protease inhibitor.
Article in International journal of pharmaceutics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 55 citations in OpenAlex.
- Functional and Physiological Implications of Oligopeptide Transporters: Potential Targets for Pharmacological Interventions.The Journal of membrane biology · 2025Review
- Pharmacokinetic Evaluation of Neutral Sphinghomyelinase2 (nSMase2) Inhibitor Prodrugs in Mice and Dogs.Pharmaceutics · 2024Article
- Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors.International journal of molecular sciences · 2023Review
- Biology of Peptide Transporter 2 in Mammals: New Insights into Its Function, Structure and Regulation.Cells · 2022Review
- Amino Acids in the Development of Prodrugs.Molecules (Basel, Switzerland) · 2018Review
- Recent advances in understanding proton coupled peptide transport via the POT family.Current opinion in structural biology · 2017Review
- Circumvention of P-gp and MRP2 mediated efflux of lopinavir by a histidine based dipeptide prodrug.International journal of pharmaceutics · 2016Article
- Prodrug approach to improve absorption of prednisolone.International journal of pharmaceutics · 2015Article
- Dipeptide prodrug approach to evade efflux pumps and CYP3A4 metabolism of lopinavir.International journal of pharmaceutics · 2014Article
- Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir.Pharmaceuticals (Basel, Switzerland) · 2014Article
- Transporter-targeted lipid prodrugs of cyclic cidofovir: a potential approach for the treatment of cytomegalovirus retinitis.Journal of pharmaceutical sciences · 2012Article
- Development of a peptide-drug conjugate for prostate cancer therapy.Molecular pharmaceutics · 2011Article
- Ocular sustained release nanoparticles containing stereoisomeric dipeptide prodrugs of acyclovir.Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics · 2011Article
- Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation.Journal of microencapsulation · 2011Article
- Interaction of ocular hypotensive agents (PGF2 alpha analogs-bimatoprost, latanoprost, and travoprost) with MDR efflux pumps on the rabbit cornea.Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics · 2009Article
- FK506-binding protein (FKBP) partitions a modified HIV protease inhibitor into blood cells and prolongs its lifetime in vivo.Proceedings of the National Academy of Sciences of the United States of America · 2009Article
- Simple, Rapid and Validated LC Determination of Lopinavir in Rat Plasma and its Application in Pharmacokinetic Studies.Scientia pharmaceuticaArticle
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Lopinavir (LVR) is extensively metabolized by CYP3A4 and is prevented from entering the cells by membrane efflux pumps such as P-gp and MRP2. In an approach to evade the first-pass metabolism and efflux of LVR, peptide prodrugs of LVR [valine-valine-lopinavir (VVL) and glycine-valine-lopinavir (GVL)] were synthesized. Prodrugs were identified with 1H and 13C NMR spectra and LC/MS/MS was employed to evaluate their mass and purity. Solubility studies indicated that the prodrugs have enhanced aqueous solubilities relative to parent LVR. Accumulation and transport data of VVL and GVL across MDCKII-MDR1 and MDCKII-MRP2 cells indicated evasion of prodrugs' efflux by P-gp and MRP2 significantly. Permeability studies across Caco-2 cells indicated that the prodrugs are transported by peptide transporters and have increased permeability as compared with LVR. VVL and GVL exhibited significantly better degradation rate constants as compared with LVR in rat liver microsomes. Enzymatic stability studies in Caco-2 cell homogenate indicated that the peptide prodrugs are first converted to the ester intermediate (amino acid prodrug VL) and then finally to the parent drug. Overall, the advantages of utilizing peptide prodrugs include chemical modification of the compound to achieve targeted delivery via peptide transporters present across the intestinal epithelium, significant evasion of efflux and CYP3A4 mediated metabolism and significantly better solubility profiles. Therefore, in vitro studies demonstrated that peptide prodrug derivatization of LVR may be an effective strategy for evading its efflux and enhancing its systemic concentrations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.