Concentration- and region-dependent intestinal permeability of fluvastatin in 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 intestine in the rat. In-situ single-pass perfusions of the jejunum, ileum and colon were performed and the effective permeability (Peff) of fluvastatin, antipyrine and D-glucose were assessed in each region, at three different perfusate fluvastatin concentrations (1.6, 16 and 160 microM). The effect of lovastatin acid on the bi-directional transport of fluvastatin across the ileal mucosa was also studied. The Peff of fluvastatin was found to be dependent both on the intestinal region and on the concentration in the intestinal lumen (P < 0.001). Fluvastatin had the lowest Peff (0.55 +/- 0.10 x 10(-4) cm s(-1)) in the jejunum at 1.6 microM, and the highest Peff (1.0 +/- 0.16 x 10(-4) cm s(-1)) in the colon at 160 microM. The highest concentration of fluvastatin increased the average absorption of water from the intestine by 209% (P < 0.05), and the average Peff of D-glucose by 29% (P < 0.05). The presence of excess lovastatin acid (100 microM, compared with fluvastatin 1.6 microM) at the luminal side increased the average absorption of water by 218% (P < 0.001), and the Peff 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 also 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-mediated process in the absorptive direction. The increased bi-directional transport when lovastatin acid was added to the lumen suggests that fluvastatin is not a P-glycoprotein substrate. Instead, the concentration-dependent increase in the absorption of fluvastatin, water and D-glucose suggests a direct effect of fluvastatin on the transcellular passive transport.
Department of Pharmacy, Biomedical Centre, Uppsala University, Sweden.
A
A
Lindahl
R
R
Sandström
A L
AL
Ungell
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H
Lennernäs
D000818:Animals; D000983:Antipyrine / Q000378:metabolism; D001692:Biological Transport; D003106:Colon / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D000077340:Fluvastatin; D005947:Glucose / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism; D007211:Indoles / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism; D008148:Lovastatin / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D008148:Lovastatin; D005947:Glucose; D000983:Antipyrine