title: The Effect of Food on the Intraluminal Behavior of Abiraterone Acetate in Man.
abstract: To relate the reported positive effect of food on the oral bioavailability of abiraterone to the intraluminal behavior of abiraterone acetate, an in vivo experiment was performed, in which duodenal fluids and plasma samples were collected from healthy volunteers after the administration of abiraterone acetate in fasted and postprandial conditions. The plasma concentration-time profiles confirmed the positive food effect. Nevertheless, intraduodenal concentrations of abiraterone acetate and abiraterone did not fully reflect this observation. This apparent discrepancy was explored by performing several in vitro experiments including solubility, dissolution, and transfer studies. Gastrointestinal transfer studies illustrated a positive impact of gastric processing of the abiraterone acetate formulation on the duodenal concentrations in the fasted state, which could not be observed in the postprandial condition. As the influence of gastric dissolution on the intraluminal concentrations in the small intestine declines aborally, it is most likely the superior solubility of abiraterone acetate and abiraterone in intestinal fluids of the fed state that dictates the food effect. Furthermore, N-oxide abiraterone sulfate and abiraterone sulfate appeared in the duodenum at significantly later time points than abiraterone, suggesting biliary excretion of these abiraterone metabolites; this was confirmed by in situ biliary excretion experiments in rats.
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Geboers
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Stappaerts
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Mols
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Janssen Research and Development, Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. Electronic address: Patrick.augustijns@pharm.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000069501:Abiraterone Acetate / Q000493:pharmacokinetics*; D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D004386:Duodenum / Q000378:metabolism; D005215:Fasting; D018565:Food-Drug Interactions; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D019518:Postprandial Period; D051381:Rats; D012995:Solubility; D065088:Steroid Synthesis Inhibitors / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D065088:Steroid Synthesis Inhibitors; D000069501:Abiraterone Acetate
keywords: abiraterone; abiraterone acetate; clinical trial; food effect; human intestinal fluids; intestinal absorption; supersaturation