Assessment of acyclovir absorption enhancement using rat single-pass intestinal perfusion model

ABSTRACT

The absorption enhancement of acyclovir [ACV], an antiviral agent, by mean of bile salt [sodium taurocholate, NaTC] and medium chain glycerides [capmul MCM, mono-/di-glycerides] was determined. MCG employing the rat model with perfused intestinal loop along with the mesenteric vein cannulation technique was used. The drug formulation containing 0.1 mM ACV were perfused through a rat intestinal segment [lower jejunum and ileum, 15 cm segment ending at the ileocecal junction] in which the corresponding mesenteric venous flow was isolated and cannulated. Each enhancer and the drug [NaTC and capmul MCM] were combined with non-ionic amphiphile surfactant with high HLB such as cremphor RH40 as a solubilizer. Collected perfusate and blood samples were analyzed for ACV by HPLC to determine intact drug concentration. The percentage absorbed [%A] and permeability coefficients corrected for surface area of absorption [intestinal radius and length] were calculated from the appearance of drug in blood [P blood] or the disappearance of drug from the perfusate as it flows through the intestinal lumen [P lumen]. Phenol red [PR] was used as a nonabsorbale marker, in a concentration of 23 mg/l, to determine net water absorption or secretion. The average C[1]/C[0] ratios [C[perfusate final concentration]/C[perfusate initial concentration]] for the perfusate suggest that the appearance of ACV in blood reaches a steady state within 15 minutes and that there is a difference in the steady state between formulations with NaTC and MCG. Both enhancers produced enhancement of ACV absorption in the rat intestine, by 3 to 4 folds for capmul and NaTC, respectively. Acyclovir permeability coefficients [P blood, cm/sec], corrected for surface area of absorption, were 4.73 +/- 0.39 x 10-6 for NaTC, 2.47 +/- 0.41 x 10-6 for MCG and 0.77 +/- 0.08 x 10-6 for perfusate without any absorption enhancer [in buffer at pH 7.5], respectively. Thus NaTC and MCG significantly increased the mucosal membrane permeability of ACV in the rat lower jejunum and ileum segment. The constant C[1]/C[0] [0.96] ratios for PR suggest that formulation did not alter intestinal water flux. These results suggest that NaTC and MCG can be used as intestinal absorption promoters for ACV in the lower jejunum and ileum which may enhance drug absorption after oral absorption, as the lack of absorption in lower jejunum and colon probably caused the lower bioavailability of ACV