RT Journal Article SR Electronic T1 Nanoparticle Formulation of a Poorly Soluble Cannabinoid Receptor 1 Antagonist Improves Absorption by Rat and Human Intestine JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1557 OP 1565 DO 10.1124/dmd.112.049585 VO 41 IS 8 A1 Sanna Siissalo A1 Hans de Waard A1 Marina H. de Jager A1 Rose Hayeshi A1 Henderik W. Frijlink A1 Wouter L.J. Hinrichs A1 Heike Dinter-Heidorn A1 Annie van Dam A1 Johannes H. Proost A1 Geny M.M. Groothuis A1 Inge A.M. de Graaf YR 2013 UL http://dmd.aspetjournals.org/content/41/8/1557.abstract AB The inclusion of nanoparticles dispersed in a hydrophilic matrix is one of the formulation strategies to improve the bioavailability of orally administered Biopharmaceutics Classification System (BCS) class II and IV drugs by increasing their dissolution rate in the intestine. To confirm that the increased dissolution rate results in increased bioavailability, in vitro and in vivo animal experiments are performed, however, translation to the human situation is hazardous. In this study, we used a range of in vitro and ex vivo methods, including methods applying human tissue, to predict the in vivo oral bioavailability of a model BCS class II CB-1 antagonist, formulated as a nanoparticle solid dispersion. The enhanced dissolution rate from the nanoparticle formulation resulted in an increased metabolite formation in both rat and human precision-cut intestinal slices, suggesting increased uptake and intracellular drug concentration in the enterocytes. In Ussing chamber experiments with human tissue, both the metabolite formation and apical efflux of the metabolite were increased for the nanoparticulate solid dispersion compared with a physical mixture, in line with the results in intestinal slices. The pharmacokinetics of the different formulations was studied in rats in vivo. The nanoparticle formulation indeed improved the absorption of the cannabinoid receptor 1 (CB-1) antagonist and the delivery into the brain compared with the physical mixture. In conclusion, the combined approach provides a valuable set of tools to investigate the effects of formulation on the absorption of poorly soluble compounds in human intestine and may provide relevant information on the oral bioavailability in humans early in the development process.