Intestinal Permeability and Presystemic Extraction of Fexofenadine and R/S-verapamil

Sammanfattning: The main objective of this thesis was to investigate the in vivo relevance of membrane transporters and cytochrome P450 (CYP) 3A4-mediated metabolism in the intestine and liver for the bioavailability of drugs in humans after oral administration.In the first part of the thesis, the main transport mechanisms involved in the intestinal absorption and bioavailability were investigated for fexofenadine, a minimally metabolized drug, which is a substrate for P-glycoprotein (P-gp) and members of organic anion transporting polypeptide (OATP) family. Jejunal perfusion studies revealed that co-perfusion with verapamil increased the bioavailability of fexofenadine by decreasing the first-pass liver extraction as the low intestinal permeability was unchanged by the transport inhibitors studied. The mechanism behind the interaction probably involves inhibition of OATP-mediated sinusoidal uptake and/or P-gp-mediated canalicular secretion of fexofenadine. Results from the Caco-2 model supported that the intestinal absorption of fexofenadine is mainly determined by the low passive permeability of the drug, even though fexofenadine clearly is a P-gp substrate. In the second part of the thesis, the effect of repeated oral administration of the P-gp and CYP3A4 inducer St. John’s wort on the in vivo intestinal permeability and presystemic metabolism of the dual P-gp and CYP3A4 substrate verapamil was investigated in a jejunal perfusion study. St. John’s wort decreased the bioavailability of the enantiomers of verapamil by inducing the CYP3A4-mediated presystemic metabolism, probably mainly in the gut. It was also concluded that induction of efflux transporters, such as P-gp, does not affect the intestinal transport or the gut wall extraction of high permeability substrates like verapamil. Data from Caco-2 cells with induced CYP3A4-activity supported these findings. The plasma levels of the enantiomers of norverapamil also decreased despite an increased formation, which was attributed to induction of CYP3A4 and/or other metabolic routes.