Comparison of pharmacokinetics of newly discovered aromatase inhibitors by a cassette microdosing approach in healthy Japanese subjects

Drug Metab Pharmacokinet. 2017 Dec;32(6):293-300. doi: 10.1016/j.dmpk.2017.09.003. Epub 2017 Sep 21.


The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development.

Keywords: Aromatase inhibitor; Cassette dosing approach; First in human study; LC–MS/MS; Microdosing clinical trial; Pharmacokinetic properties.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Aged
  • Anastrozole
  • Aniline Compounds / administration & dosage
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacokinetics*
  • Animals
  • Aromatase / metabolism*
  • Aromatase Inhibitors / administration & dosage
  • Aromatase Inhibitors / chemistry
  • Aromatase Inhibitors / pharmacokinetics*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Healthy Volunteers
  • Humans
  • Japan
  • Male
  • Molecular Structure
  • Nitriles / administration & dosage
  • Nitriles / chemistry
  • Nitriles / pharmacokinetics*
  • Rats
  • Structure-Activity Relationship
  • Triazoles / administration & dosage
  • Triazoles / chemistry
  • Triazoles / pharmacokinetics*


  • Aniline Compounds
  • Aromatase Inhibitors
  • Nitriles
  • Triazoles
  • cetrozole
  • Anastrozole
  • Aromatase
  • CYP19A1 protein, human