Abiraterone acetate (AA) is a prodrug of abiraterone, a selective and potent steroidal cytochrome P450 17alpha- hydroxylase-17,20-lyase (CYP17A1) blocking androgen synthesis in the treatment of advanced prostate cancer. Abiraterone (Abi) is metabolized to D(4)-abiraterone (D4A) directly blocking CYP17A1 and other steroidogenic enzymes and antagonizing the androgen receptor (AR). D4A is converted by 5α-reductase to 3-keto-5α-abiraterone (5α-Abi), an AR agonist. Our recent work suggests phase II biotransformation of Abi, D4A and 5α-Abi conjugated to glucuronic acid in vitro leading to four glucuronides (G). We developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a 6500 Qtrap mass analyzer coupled with a Shimadzu Nexera system for quantification of Abi, its active metabolites and their G derivatives in human plasma samples with deuterated internal standards. Validation was carried out according to FDA guidelines for bioanalytical method and results were within the acceptance limits. Analytes were extracted from 50 μL of plasma using a solid phase extraction procedure. Multiple reaction monitoring was used with electrospray ionization in a positive mode. Linearity, precision, and accuracy were validated over a large range of concentrations for each compound (range of 0.5-100 ng/mL for Abi and for metabolites and 0.05-10.00 ng/mL for glucuronides). The method could measure all seven analytes with sensitivity, accuracy (87-106%), and reproducibility (CV < 10.7%). Its clinical application was further examined with plasma samples obtained from prostate cancer patients under AA treatment. This reliable and validated LC-MS/MS method could be a useful tool for human biomonitoring studies.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2018 Dec 04 [Epub ahead of print]
Patrick Caron, Véronique Turcotte, Eric Lévesque, Chantal Guillemette
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire (CHU) de Québec, - Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec city, QC, Canada., CHU de Québec Research Center and Faculty of Medicine, Laval University, Québec city, QC, Canada., Pharmacogenomics Laboratory, Centre Hospitalier Universitaire (CHU) de Québec, - Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec city, QC, Canada; Canada Research Chair in Pharmacogenomics, Canada. Electronic address: .