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.
1. The aim of the current study was to investigate the characteristics of biliary excretion of antofloxacin (ATFX) in rats. Rats received a bolus intravenous injection followed by a constant-rate infusion of ATFX. When plasma concentrations of ATFX reached steady state, cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac were administered intravenously to the rats. Samples of blood and bile were collected and the concentrations of ATFX were measured and the corresponding pharmacokinetic parameters were estimated. 2. Biliary excretion of ATFX was observed in rats subjected to CCl(4)-induced experimental hepatic injury for 24 h (CCl(4)-EHI(24h)). Steady state concentrations of ATFX were attained at 60 min following infusion. 3. A slight increase in concentration of ATFX in plasma was observed after cyclosporin A, erythromycin, probenecid and cimetidine treatment. Significant increases in ATFX plasma levels were found in rats treated with diclofenac. Cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac treatment significantly decreased the steady state biliary clearance of ATFX to 55, 68, 54, 53 and 56% of control values, respectively. 4. Cyclosprin A, probenecid, erythromycin and cimetidine also inhibited the biliary excretion of ATFX glucuronide. Significant decrease in the steady state biliary clearance of ATFX and its glucuronide was observed in CCl(4)-EHI(24h) rats. 5. These results indicate that multiple transporters are possibly involved in the biliary excretion of ATFX.
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