Absorption, distribution, metabolism and excretion of darolutamide (a novel non-steroidal androgen receptor antagonist) in rats

• Published in: Xenobiotica Vol. 50; no. 8; pp. 967 - 979
• Main Authors: Taavitsainen, Päivi, Gieschen, Hille, Korjamo, Timo, Kähkönen, Marja, Malmström, Chira, Prien, Olaf, Niehues, Michael, Sandmann, Steffen, Janssen, Wiebke, Koskinen, Mikko
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.08.2020
• Subjects: Absorption; androgen receptor antagonist; autoradiography; blood-brain barrier; distribution; metabolism and excretion (ADME); pharmacokinetics; preclinical; rats; Absorption; blood–brain barrier; autoradiography; preclinical; metabolism and excretion (ADME); androgen receptor antagonist; pharmacokinetics; rats; distribution
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/00498254.2020.1723038

1. Darolutamide is a novel selective androgen receptor antagonist consisting of two pharmacologically equipotent diastereoisomers. The absorption, distribution, metabolism and excretion properties of darolutamide in rats are reported. 2. Non- or [ 14 C]-labelled darolutamide, its diastereoisomers and major metabolite were studied in intact and bile duct-cannulated rats (oral and intravenous administration), and rat hepatocytes. 3. Darolutamide was quickly (1 h to reach maximum plasma concentration) and completely absorbed after oral administration. Absolute bioavailability was high. Keto-darolutamide was the most abundant metabolite in rat hepatocytes and the only major one in plasma. Interconversion between diastereoisomers was observed. 4. After oral administration, radioactivity distributed widely and homogeneously. Penetration into brain was low (brain/blood ratio = 0.079). Elimination was rapid from most tissues. Excretion occurred rapidly, and routes were similar irrespective of administration routes. Complete mass balance was reached by 168 h post-dose. Most radioactivity (61-64%) was excreted in faeces, while relevant amounts (30-33%) were also excreted into urine. The main clearance routes were metabolism via oxidative reactions and glucuronidation. After intravenous administration, a relevant extent of the dose (20%) underwent extrabiliary excretion as darolutamide.