Enhancing effect of Labrasol on the intestinal absorption of ganciclovir in rats

Abstract

Ganciclovir (GCV), like other nucleoside analogs such as trifluridine and acyclovir (ACV), is hydrophilic, poorly permeable across membranes and orally low-bioavailable. In the present studies, Labrasol was evaluated for improving intestinal absorption of GCV through in vitro and in vivo experiments. The effect of Labrasol on absorption of GCV in rat small intestine was investigated using an in situ single-pass perfusion technique. The apparent absorptive clearance (PeA) of GCV with Labrasol in the duodenum, jejunum and ileum was 1.01, 1.28, and 1.49 mL/min/cm (n = 6), respectively, and significant regional differences of GCV absorption among the three segments were observed p jejunum, p duodenum (p > 0.05). The effects of EDTA, verapamil on the permeability of GCV were conducted. The permeability of GCV was increased by EDTA, verapamil, respectively. The results indicated that paracellular absorption and efflux played important roles in GCV absorption. In vivo absorption GCV in rats was conducted. When GCV at 1 mg/kg dose was administered with Labrasol (10%, v/v), the mean AUC of was determined as 14.45 ± 3.88 μg*h/mL, compared to 8.05 ± 1.52 µg*h/mL without Labrasol. Based on the results, we could conclude that the absorption of GCV through GI lumen would be enhanced by Labrasol. The effect of Labrasol maybe ascribed to both (i) inhibit efflux of GCV from the enterocytes to the GI lumen; and (ii) enhance GCV absorption from the GI lumen through paracellular pathway.

Gintonin absorption in intestinal model systems

“…These additional routes in the intestine might include the paracellular pathway and energy-dependent pathways such as transporter-mediated transport. Since gintonin-mediated LPA receptor activation is coupled to the activation of Rho kinase [4] , which is known to induce morphological changes in cells via filamentous actin reorganization and opening of intercellular tight junctions in the epithelium (the main barrier of the paracellular pathway) [18] , [19] , [20] , we examined the effect of a Rho kinase inhibitor on gintonin intestinal absorption. As shown in Fig.…”

Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

“…Moreover, the enhanced permeability of the Caco-2 cell monolayer to the powder formulation may indicate Labrasol-induced inhibition of glucuronidation. This inhibition opens junctions via interactions with filamentous actin and the zonula occludens-1 protein, and inhibits secretory transport from enterocytes [47,48,49,50]. Also, Labrasol and P188 may enhance permeation by altering intestinal membrane lipid fluidity and (reversibly) perturbing the epithelial plasma membrane [43,50].…”

The Ameliorated Pharmacokinetics of VP-16 in Wistar Rats: A Possible Role of P-Glycoprotein Inhibition by Pharmaceutical Excipients

“…Based on our findings, Labrasol was found to have the strongest inhibitory effect on P-gp efflux function among other pharmaceutical excipients used in this study. It was reported basolateral-to-apical efflux inhibition by Labrasol was responsible for permeation enhancement of a poorly permeable drug, ganciclovir [24]. Although multiple mechanisms are undoubtedly responsible for the mechanism of permeability transport of P-gp substrates via excipients, this may partially involve the modulating of the membrane lipid fluidity or passive transport via both a [25,26].…”