In:
Drug Metabolism Letters, Bentham Science Publishers Ltd., Vol. 14, No. 1 ( 2021-05-05), p. 9-16
Kurzfassung:
Saini et al. recently investigated the pharmacokinetics of darolutamide
and its diastereomers in vitro and in vivo in Balb/c mice, reporting higher levels of (S,S)-darolutamide than (S,R)-darolutamide following intravenous or oral dosing, and interconversion of
(S,R)-darolutamide to (S,S)-darolutamide. Objective: To present our in vitro and in vivo studies of darolutamide pharmacokinetics in mice,
which contrast with the findings of Saini et al. Methods: Nude male Balb/c mice were orally dosed for 7 days with 25, 50, or 100 mg/kg of darolutamide
twice daily. Pharmacokinetic parameters in plasma and tissue samples were assessed by liquid chromatography-tandem mass spectrometry. Metabolism and interconversion of darolutamide
and its diastereomers were investigated in cryopreserved Balb/c mouse hepatocytes. Protein binding was determined in plasma samples by equilibrium dialysis. Results : On day 7, C max was reached 30 min after the last dose. Rapid formation and greater exposure
of keto-darolutamide versus darolutamide were observed. Plasma exposure of (S,R)-darolutamide was 3-5-fold higher than that of (S,S)-darolutamide. The fraction of unbound keto-darolutamide
was almost 6-fold lower than for darolutamide. Conclusion: The darolutamide diastereomer ratio changes upon administration in mice and other
species due to interconversion through keto-darolutamide. This is not considered clinically relevant since both diastereomers and keto- darolutamide are pharmacologically similar in vitro. Based on
the high protein binding of keto-darolutamide, its contribution in vivo in humans is considered low.
Materialart:
Online-Ressource
ISSN:
1872-3128
DOI:
10.2174/1872312814666201112121129
Sprache:
Englisch
Verlag:
Bentham Science Publishers Ltd.
Publikationsdatum:
2021
SSG:
15,3
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