title: Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: in vitro, rat in situ and human in vivo studies.
abstract: The aim of this study was to evaluate the intestinal disposition of abiraterone acetate, an ester prodrug of the anticancer agent abiraterone. Stability of the prodrug and solubility and dissolution characteristics of both abiraterone and abiraterone acetate were monitored in vitro. Moreover, the in vivo intraluminal concentrations of abiraterone and abiraterone acetate upon intake of one tablet of 250 mg abiraterone acetate were assessed in healthy volunteers. The intestinal absorption resulting from the intraluminal behavior of the ester prodrug was determined using the rat in situ intestinal perfusion technique with mesenteric blood sampling. Simulated and aspirated human intestinal fluids of the fasted state were used as solvent systems. Upon incubation of abiraterone acetate in human intestinal fluids in vitro, rapid hydrolysis of the prodrug was observed, generating abiraterone concentrations largely exceeding the apparent solubility of abiraterone, suggesting the existence of intestinal supersaturation. These findings were confirmed in vivo, by intraluminal sampling of duodenal fluids upon oral intake of an abiraterone acetate tablet by healthy volunteers. Rat in situ intestinal perfusion experiments performed with suspensions of abiraterone and abiraterone acetate in human intestinal fluids of the fasted state revealed significantly higher flux values upon perfusion with the prodrug than with abiraterone. Moreover, rat in situ intestinal perfusion with abiraterone acetate suspensions in simulated fluids of the fasted state in presence or absence of esterases demonstrated that increased hydrolytic activity of the perfusion medium was beneficial to the intestinal absorption of abiraterone. In conclusion, the rapid hydrolysis of abiraterone acetate in the intraluminal environment appears to result in fast and extensive generation of abiraterone supersaturation, creating a strong driving force for abiraterone absorption.
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Stappaerts
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Geboers
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Janssen Research and Development, Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.affiliation: Department of Gastroenterology, University Hospitals Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. Electronic address: patrick.augustijns@pharm.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000069501:Abiraterone Acetate / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D004952:Esters / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D055815:Young Adult
chemical_list: D004952:Esters; D011355:Prodrugs; D000069501:Abiraterone Acetate
keywords: Abiraterone; Ester prodrug; Human intestinal fluids; Intestinal perfusion; Intraluminal degradation; Intraluminal supersaturation