Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

Abstract

Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, ValVal-SQV and Gly-Val-SQV. Equimolar concentration (25 μM) of SQV, Val-Val-SQV and GlyVal-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 μM) and glycyl-sarcosine (20mM). Absorption rate constants in rat jejunum (k a ) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1±3.4 ×10 −3 , 65.8±4.3 ×10 −3 , and 25.6±5.7 ×10 −3 min −1 respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 μM (P-gp inhibitor). However, permeability of ValVal-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.

Intestinal absorption of forsythoside A in in situ single-pass intestinal perfusion and in vitro Caco-2 cell models

“…Pluronic block copolymers, like Pluronic F68, could inhibit P-gp/CYP3A4 [38] . In addition, prodrug designations, like peptide prodrug modifications, could also shield FTA from the efflux pump [39] . Therefore, investigations into improving the permeability of FTA using pharmaceutical methods based on the above research and evaluating the toxicity of pharmaceutical excipients (functional excipients or additives) are required to improve the oral BA of FTA.…”

Effects of Pluronic F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin in rats

“…The surgical procedure and in situ single-pass perfusion experiments were performed according to previously described methods (Sutton et al, 2001;Issa et al, 2003;Jain et al, 2007). After anesthesia via intraperitoneal administration of urethane (10 mg/kg), rats were placed on a heating pad to maintain body temperature at 37 o C. The abdomen was opened with a midline longitudinal incision.…”

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

“…The intestinal absorption of Val-Val-SQV was significantly suppressed in the presence of Gly-Sar, indicating the involvement of PEPT1 in intestinal absorption of Val-Val-SQV. 108 The interaction of dipeptide prodrugs with MRP2 was examined using MDCKII-MRP2 cell monolayer. Uptake studies indicated that dipeptide prodrugs of SQV have significantly lower affinity toward MRP2 compared to SQV.…”