Intestinal transport and hepatic extraction of fluvastatin in humans and rats

Abstract: The oral route is the most convenient route of delivering drugs intended to have systemic effects. One of the key variables determining the rate and extent of absorption from the gastrointestinal tract is the intestinal permeability to the drug. Following intestinal absorption, the drug may be extracted, metabolised and/or secreted by transport proteins and/or enzymes located in the intestinal wall and in the liver. The main objectives of this thesis were to characterise the intestinal effective permeability (Peff) the absorption mechanism(s) and the hepatic extraction offluvastatin, a drug used for the treatment of hypercholesterolemia.The intestinal Peff of fluvastatin was investigated in anaesthetised rats with use of an in situ single-pass perfusion technique and in conscious male volunteers using an in vivo jejunal perfusion technique (Loc-I-Gut®). In the rats, the regional Peff of fluvastatin was studied in the jejunum, ileum and colon at various lumenal concentrations. The possible involvement of the monocarboxylic acid transporter (MCT); the P-glycoprotein (Pgp) and the multidrug resistance associated protein (MRP) in the intestinal transport of fluvastatin was examined in the rat. The hepatic extraction of fluvastatin during the first-pass was estimated in both rats and humans in vivo.Fluvastatin has a high intestinal Peff in the human jejunum and in all the regions of the rat intestine investigated here. The Peff is concentration- and region-dependent in the rat, with the highest permeability being in the colon at the highest lumenal concentration. This concentration dependence is probably not caused by the involvement of the efflux proteins Pgp and MRP. The ability of fluvastatin to decrease the surface tension of the intestinal perfusion solution can partly explain the concentration-dependent Peff. The MCT does not transport fluvastatin to any significant extent in the rat intestine.Fluvastatin is extracted to approximately 70% and 30-50% during the first-pass in humans and rats, respectively. This extraction occurs most likely in the liver. The high degree of hepatic extraction of fluvastatin might be beneficial for the treatment of hypercholesterolemia, as the liver is the major site for the biosynthesis of cholesterol.