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Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of [14C]aficamten following single oral dose administration to rats.
- Source :
-
Xenobiotica . Sep2024, Vol. 54 Issue 9, p670-685. 16p. - Publication Year :
- 2024
-
Abstract
- The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [14C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats. [14C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC0–48). Plasma tmax was 4-h and the t1/2 of total plasma radioactivity was 5.8-h. Tissues showing highest Cmax exposures were myocardium and semitendinosus muscle. Most [14C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively. In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed. [14C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00498254
- Volume :
- 54
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- Xenobiotica
- Publication Type :
- Academic Journal
- Accession number :
- 180591125
- Full Text :
- https://doi.org/10.1080/00498254.2024.2381111