Metabolism and Mass Balance of the Novel Nonsteroidal Androgen Receptor Inhibitor Darolutamide in Humans.

Autor:	Taavitsainen P; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Prien O; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Kähkönen M; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Niehues M; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Korjamo T; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Denner K; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Nykänen P; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Vuorela A; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Jungmann NA; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., von Bühler CJ; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Koskinen M; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Zurth C; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.)., Gieschen H; Orion Corporation Orion Pharma, Turku, Finland (P.T.); Bayer AG, Berlin, Germany (O.P., M.N., K.D., C.Z., H.G.); Orion Corporation Orion Pharma, Espoo, Finland (M.K., T.K., P.N., A.V., M.K.); and Bayer AG, Wuppertal, Germany (N.A.J., C.-J.v.B.) hille.gieschen@bayer.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2021 Jun; Vol. 49 (6), pp. 420-433. Date of Electronic Publication: 2021 Mar 30.
DOI:	10.1124/dmd.120.000309
Abstrakt:	The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14 C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatography mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of ( S , R )- and ( S , S )-darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O -glucoronide (M-7a/b) and N -glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of ( S , S )-darolutamide. SIGNIFICANCE STATEMENT: The metabolism and excretion of darolutamide in humans revealed that oxidation (CYP3A4) and glucuronidation (UGT1A9, UGT1A1) were the main metabolic routes of elimination. Direct excretion also contributed to overall clearance. The two pharmacologically equipotent diastereomers of darolutamide interconvert primarily via oxidation to the active metabolite keto-darolutamide, followed by reduction predominantly by cytosolic reductase(s). The latter reaction showed stereoselectivity with preferential formation of ( S,S )-darolutamide. Data indicate a low drug-drug interaction potential of darolutamide with inducers or inhibitors of metabolizing enzymes. Competing Interests: Clemens-Jeremias von Bühler and Natalia Jungmann report employment by Bayer. Hille Gieschen, Karsten Denner, and Christian Zurth report employment by and stock ownership in Bayer. Michael Niehues and Olaf Prien are employed by NUVISAN, Inc., but were employees of Bayer, and Dr. Prien held stock in Bayer at the time that the work was performed. Marja Kähkönen, Pirjo Nykänen, Päivi Taavitsainen, and Annamari Vuorela report employment by Orion. Timo Korjamo and Mikko Koskinen report employment by and stock ownership in Orion. (Copyright © 2021 by The Author(s).)
Databáze:	MEDLINE
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