%0 Journal Article
%T Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of [14C]aficamten following single oral dose administration to rats.
%A Grillo MP
%A Sukhun R
%A Bashir M
%A Ashcraft L
%A Morgan BP
%J Xenobiotica
%V 0
%N 0
%D 2024 Aug 7
%M 39058619
%F 1.997
%R 10.1080/00498254.2024.2381111
%X 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.