Peptide prodrugs: improved oral absorption of lopinavir, a HIV protease inhibitor.

摘要: Abstract Lopinavir (LVR) is extensively metabolized by CYP3A4 and prevented from entering the cells membrane efflux pumps such as P-gp MRP2. In an approach to evade first-pass metabolism of LVR, peptide prodrugs LVR [valine–valine–lopinavir (VVL) glycine–valine–lopinavir (GVL)] were synthesized. Prodrugs identified with 1H 13C NMR spectra LC/MS/MS was employed evaluate their mass purity. Solubility studies indicated that have enhanced aqueous solubilities relative parent LVR. Accumulation transport data VVL GVL across MDCKII-MDR1 MDCKII-MRP2 evasion prodrugs’ MRP2 significantly. Permeability Caco-2 are transported transporters increased permeability compared exhibited significantly better degradation rate constants in rat liver microsomes. Enzymatic stability cell homogenate first converted ester intermediate (amino acid prodrug VL) then finally drug. Overall, advantages utilizing include chemical modification compound achieve targeted delivery via present intestinal epithelium, significant mediated solubility profiles. Therefore, vitro demonstrated derivatization may be effective strategy for evading its enhancing systemic concentrations.