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Pharmaceuticals 2014, 7(4), 433-452;

Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA
Author to whom correspondence should be addressed.
Received: 23 January 2014 / Revised: 24 March 2014 / Accepted: 31 March 2014 / Published: 10 April 2014
(This article belongs to the Special Issue Prodrugs: from Design to Clinic)
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Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2. View Full-Text
Keywords: lopinavir; LPV; prodrug; uptake; transport; permeability; efflux; P-gp; MRP2 lopinavir; LPV; prodrug; uptake; transport; permeability; efflux; P-gp; MRP2

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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Patel, M.; Mandava, N.; Gokulgandhi, M.; Pal, D.; Mitra, A.K. Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir. Pharmaceuticals 2014, 7, 433-452.

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