Investigations of the mechanism behind the rapid absorption of nano-amorphous abiraterone acetate

Eur J Pharm Sci. 2019 Mar 1;129:79-86. doi: 10.1016/j.ejps.2019.01.001. Epub 2019 Jan 2.


Abiraterone acetate is indicated for patients with metastatic castration resistant prostate cancer. The marketed drug product (Zytiga®) exhibits very low bioavailability in the fasted state and a substantial positive food effect. We recently developed a nano-amorphous formulation of this drug which exhibited higher apparent solubility and dissolution rate, and significantly improved absorption and bioavailability in the fasted state in beagle dogs and in a phase I clinical study. One surprising finding, however, was the very rapid absorption observed both in dogs and in humans with median tmax values in the 0.5-0.75 h range. This could not be explained by the improved dissolution characteristics alone. A recent study showed that following the administration of Zytiga® abiraterone acetate is converted to abiraterone in the intestinal lumen yielding supersaturated abiraterone concentrations, which is believed to be the driving force of the absorption process. In our work we found that the enzymatic hydrolysis of abiraterone acetate profoundly changes the pharmacokinetics of the nano-amorphous formulation in the fasted state and it is the most probable reason for the unexpectedly high absorption rate. Our primary candidate for the isoenzyme involved is pancreatic cholesterol esterase. Furthermore, we identified orlistat as a potent inhibitor of cholesterol esterase and found it to be an ideal compound for the study of the enzymatic process in vivo. The observed inhibition could result in a clinically significant modification of abiraterone pharmacokinetics, which might make a drug interaction warning necessary for abiraterone acetate containing drugs. The mathematical and experimental tools presented in this work might be suitable for the study of the contribution of other intestinal enzymatic processes to the absorption process of other prodrugs as well.

Keywords: Abiraterone acetate; Cholesterol esterase; Intestinal enzymatic hydrolysis; Nano-amorphous formulation; Orlistat.

MeSH terms

  • Abiraterone Acetate / pharmacokinetics
  • Abiraterone Acetate / pharmacology*
  • Animals
  • Biological Availability
  • Dogs
  • Food-Drug Interactions / physiology
  • Humans
  • Intestines / drug effects
  • Male
  • Nanoparticles / administration & dosage*
  • Pancreas / metabolism
  • Solubility
  • Sterol Esterase / metabolism


  • Sterol Esterase
  • Abiraterone Acetate