Abstract

The first purpose of this study was to investigate the in vivo absorption, biliary secretion, and first-pass effect of fluvastatin following regional intestinal dosing in the rat. We also examined the membrane transport mechanisms and made in silico predictions of the relative importance of various intestinal regions to the human absorption of fluvastatin. Fluvastatin was administered intravenously (2, 10, and 20 μmol/kg) and into the duodenum (1.46, 2.92, 7.32, and 14.6 μmol/kg), jejunum (14.6 μmol/kg), ileum (1.46 and 14.6 μmol/kg), and colon (1.46 and 14.6 μmol/kg) as a solution to conscious rats. In a separate group of rats, bile was collected after an iv dose of fluvastatin (2 μmol/kg). In the Caco-2 model the bidirectional transport of fluvastatin (16 μM) was investigated with and without various efflux inhibitors (verapamil, vinblastine, probenecid, and indomethacin, 160 μM). The human in vivo absorption of fluvastatin from an oral immediate release tablet and that from an oral extended release tablet (both 40 mg) were simulated in GastroPlus. Neither the dose nor the intestinal region influenced the bioavailability of fluvastatin significantly. The rate of absorption was, however, affected by both the dose and the site of administration; duodenum = jejunum > colon > ileum, and higher following the high dose. Increasing the iv dose from 2 to 20 μmol/kg decreased the clearance (26 ± 3 to 12 ± 1 mL/min/kg), the hepatic extraction (66 ± 8 to 30 ± 2%), and the volume of distribution (7.3 ± 0.3 to 2.1 ± 0.7 L/kg) for fluvastatin (p < 0.05). Neither bile cannulation nor bile sampling affected the pharmacokinetics. Fluvastatin was secreted into the bile, probably by active transport. The in vitro permeability for fluvastatin was high (>10 × 10^–6 cm/s). Indomethacin, but not the other inhibitors, affected the transport in both directions suggesting mrp2 to be involved. In silico, 93% of the dose was absorbed from the small intestine and 6% from the colon when given as an immediate release formulation. The corresponding values for an extended release formulation were 21% and 74%, respectively. In conclusion, fluvastatin exhibits dose-dependent pharmacokinetics in the rat. The rate of absorption (C_max, T_max, and C_max/AUC_lqc) from the intestinal tract is both region and dose-dependent in the rat. This may be due to the involvement of mrp2 in the intestine and/or in the liver. These absorption properties have to be considered in the development of an extended release formulation of fluvastatin.