RT Journal Article
SR Electronic
T1 Application of Accelerator Mass Spectrometry to Characterize the Mass Balance Recovery and Disposition of AZD4831, a Novel Myeloperoxidase Inhibitor, Following Administration of an Oral Radiolabeled Microtracer Dose in Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2022-001100
DO 10.1124/dmd.122.001100
A1 Bhattacharya, Chandrali
A1 Sandinge, Ann-Sofie
A1 Bragg, Ryan A.
A1 Heijer, Maria
A1 Yan, Jingjing
A1 Andersson, Linda C.
A1 Jurva, Ulrik
A1 Pelay-Gimeno, Marta
A1 Vaes, Wouter H.J.
A1 de Ligt, Rianne A.F.
A1 Gränfors, Malin
A1 Amilon, Carl
A1 Lindstedt, Eva-Lotte
A1 Menakuru, Somasekhara R.
A1 Garkaviy, Pavlo
A1 Weidolf, Lars
A1 Gopaul, V. Sashi
YR 2023
UL http://dmd.aspetjournals.org/content/early/2023/01/13/dmd.122.001100.abstract
AB This study evaluated the mass balance and disposition of AZD4831, a novel myeloperoxidase inhibitor, in six healthy participants using a 14C-labeled microtracer coupled with analysis by accelerator mass spectrometry (AMS). A single oral dose of 10 mg 14C‑AZD4831 (14.8 kBq) was administered as a solution, and 14C levels were quantified by AMS in blood, urine, and feces over 336 hours post-dose. AZD4831 was rapidly absorbed and AZD4831 plasma concentrations declined in a biphasic manner, with a long half-life of 52 hours. AZD4831 was eliminated via metabolism and renal excretion. An N-carbamoyl glucuronide metabolite of AZD4831 (M7), formed primarily via UGT1A1, was the predominant circulating metabolite. Presumably, M7 contributed to the long half-life of AZD4831 via biliary elimination and hydrolysis/enterohepatic recirculation of AZD4831. On average, ~84% of administered 14C‑AZD4831 was recovered by 336 hours post-dose (urine 51.2%; feces 32.4%). Between 32-44% of the dose was excreted as unchanged AZD4831 in urine, indicating renal elimination as the major excretory route. Only 9.7% of overall fecal recovery was recorded in the first 48 hours, with the remainder excreted over 48-336 hours, suggesting most fecal recovery was due to biliary elimination. Furthermore, only 6% of unchanged AZD4831 was recovered in feces. Overall, the fraction of the administered AZD4831 dose absorbed was high. 14C-AZD4831 was well tolerated. These findings contribute to increasing evidence that human absorption, distribution, metabolism, and excretion studies can be performed with acceptable mass balance recovery at therapeutically relevant doses and low radiolabel specific activity using an AMS-14C microtracer approach. Significance Statement In this study, the human absorption, distribution, metabolism, and excretion (hADME) of the novel myeloperoxidase inhibitor, AZD4831, was assessed following oral administration. This included investigation of the disposition of M7, the N-carbamoyl glucuronide metabolite. Resolution of challenges highlighted in this study contributes to increasing evidence that hADME objectives can be achieved in a single study for compounds with therapeutically relevant doses and low radiolabel specific activity by using an AMS‑14C microtracer approach; thus, reducing the need for preclinical radiolabeled studies.