Dipeptide prodrug approach to evade efflux pumps and CYP3A4 metabolism of lopinavir
| Autor: | Nanda K. Mandava, Dhananjay Pal, Mitesh Patel, Ye Sheng, Ashim K. Mitra |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B Time Factors Pharmaceutical Science Peptide Lopinavir Article Madin Darby Canine Kidney Cells chemistry.chemical_compound Dogs Drug Stability Animals Cytochrome P-450 CYP3A Humans Prodrugs ATP Binding Cassette Transporter Subfamily B Member 1 chemistry.chemical_classification Dipeptide Dose-Response Relationship Drug Chemistry Multidrug resistance-associated protein 2 Biological Transport Transporter Dipeptides HIV Protease Inhibitors Metabolism Hydrogen-Ion Concentration Prodrug Enzyme Biochemistry Microsomes Liver Efflux Caco-2 Cells |
| Zdroj: | International Journal of Pharmaceutics. 476:99-107 |
| ISSN: | 0378-5173 |
| DOI: | 10.1016/j.ijpharm.2014.09.035 |
| Popis: | Oral absorption of lopinavir (LPV) is limited due to P-glycoprotein (P-gp) and multidrug resistance-associated protein2 (MRP2) mediated efflux by intestinal epithelial cells. Moreover, LPV is extensively metabolized by CYP3A4 enzymes. In the present study, dipeptide prodrug approach was employed to circumvent efflux pumps (P-gp and MRP2) and CYP3A4 mediated metabolism of LPV. Valine–isoleucine–LPV (Val–Ile–LPV) was synthesized and identified by LCMS and NMR techniques. The extent of LPV and Val–Ile–LPV interactions with P-gp and MRP2 was studied by uptake and transport studies across MDCK–MDR1 and MDCK–MRP2 cells. To determine the metabolic stability, time and concentration dependent degradation study was performed in liver microsomes. Val–Ile–LPV exhibited significantly higher aqueous solubility relative to LPV. This prodrug generated higher stability under acidic pH. Val–Ile–LPV demonstrated significantly lower affinity toward P-gp and MRP2 relative to LPV. Transepithelial transport of Val–Ile–LPV was significantly higher in the absorptive direction (apical to basolateral) relative to LPV. Importantly, Val–Ile–LPV was recognized as an excellent substrate by peptide transporter. Moreover, Val–Ile–LPV displayed significantly higher metabolic stability relative to LPV. Results obtained from this study suggested that dipeptide prodrug approach is a viable option to elevate systemic levels of LPV following oral administration. |
| Databáze: | OpenAIRE |
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