Concentration- and region-dependent intestinal permeability of fluvastatinin the rat

The purpose of this study was to investigate the mechanisms of transport of fluvastatin across the intestinal mucosa in various regions of the intesti ne in the rat. In-situ single-pass perfusions of the jejunum, ileum and col on were performed and the effective permeability (P-eff) of fluvastatin, an tipyrine and D-glucose were assessed in each region, at three different per fusate fluvastatin concentrations (1.6, 16 and 160 mu M). The effect of lov astatin acid on the bi-directional transport of fluvastatin across the ilea l mucosa was also studied. The P-eff of fluvastatin was found to be dependent both on the intestinal r egion and on the concentration in the intestinal lumen (P<0.001). Fluvastat in had the lowest P-eff (0.55 +/- 0.10 x 10(-4) cm s(-1)) in the jejunum at 1.6 mu M, and the highest P-eff (1.0 +/- 0.16 x 10(-4) cm s(-1)) in the co lon at 160 mu M. The highest concentration of fluvastatin increased the ave rage absorption of water from the intestine by 209% (P < 0.05), and the ave rage P-eff of D-glucose by 29% (P < 0.05). The presence of excess lovastati n acid (100 mu M, compared with fluvastatin 1.6 mu M) at the luminal side i ncreased the average absorption of water by 218% (P < 0.001), and the P-eff of fluvastatin in the ileum and the colon by 44 and 50%, respectively (P < 0.05). The presence of lovastatin acid on the luminal side in the ileum al so increased the blood-to-lumen transport (exsorption) of fluvastatin by 43 % (P < 0.001). The increased intestinal absorption of fluvastatin at higher concentrations does not suggest that substantial absorption occurs by any carrier-mediate d process in the absorptive direction. The increased bi-directional transpo rt when lovastatin acid was added to the lumen suggests that fluvastatin is not a P-glycoprotein substrate. Instead, the concentration-dependent incre ase in the absorption of fluvastatin, water and D-glucose suggests a direct effect of fluvastatin on the transcellular passive transport.