Intestinal permeability and presystemic metabolism of R/S-verapamil and fluvastatin

Sammanfattning: The rate and extent of absorption of drugs from the gastrointestinal tract into the systemiccirculation is defined as the bioavailability. The bioavailability is influenced by a numberof pharmaceutical, pharmacokinetic, biochemical and physiological factors. Two key-variables are the intestinal permeability and the presystemic metabolism. The intestinal permeability describes the transport of a drug across the enterocytes. The permeability isdependent on the properties of the drug molecule, the composition of the cell membraneand the mechanism involved in the membrane transport. The presystemic metabolism ismainly located in the intestinal wall and the liver. The most common enzymes involved indrug metabolism belong to the cytochrome P450 family.Intestinal permeability of each enantiomer of verapamil and the racemat of fluvastatinwere investigated in humans and rats using single-pass perfusion techniques. The first-pass metabolism was investigated in humans during the perfusion studies. In humans, apreviously validated in vivo jejunal perfusion technique was used. In rats, an in situperfusion technique was used in anaesthetised animals. The intestinal permeability offluvastatin and verapamil were determined at different perfusate concentrations. Fluvastatinwas also investigated in different regions of the intestine and at different concentrations inrats.The jejunal permeability values of verapamil and fluvastatin were high and concentration dependent. This is most likely explained by saturation in the P-glycoprotein mediatedefflux for R- and S-verapamil in both species. For fluvastatin it seems as though otherfactors related to a physiochemical interaction between the drug and the cell membranegives a plausible explanation in the rat. The first-pass metabolism in humans was extensive for both drugs. R- and S-verapamil were metabolised in both the gut wall and theliver. Ketoconazole did not affect the human jejunal permeability, but inhibited thepresystemic metabolism in the gut wall for R/S-verapamil. Fluvastatin was primarilymetabolised in the liver with little or no contribution from the intestinal wall.