Publication Cover
Xenobiotica
the fate of foreign compounds in biological systems
Volume 51, 2021 - Issue 10
169
Views
0
CrossRef citations to date
0
Altmetric
Animal Pharmacokinetics and Metabolism

Pharmacokinetics and metabolic disposition of a potent and selective kynurenine monooxygenase inhibitor, CHDI-340246, in laboratory animals

ORCID Icon, , , , , , & show all
Pages 1155-1180 | Received 07 Jul 2021, Accepted 03 Sep 2021, Published online: 15 Sep 2021
 

Abstract

  1. The disposition of a novel kynurenine monooxygenase inhibitor, CHDI-340246, was investigated in vitro and in animals.

  2. In vitro, there was minimal metabolic turnover of CHDI-340246 in all species. The protein binding was higher in human plasma (99.7%) relative to other species.

  3. In all species, blood clearance was low (<20% of liver blood flow) and volume of distribution was small (<0.5 L/kg). The terminal half-life was longer in monkeys (9 hr) than in mice, rats, or dogs (1–2 hr). CHDI-340246 was orally bioavailable (>60%) in all species.

  4. In rats, [14C]CHDI-340246 showed wide distribution of radioactivity in all tissues except brain and testes. In rats, the parent drug was the major circulating moiety with minor amounts of a sulphate conjugate of an O-dealkylated metabolite. The elimination occurred via the urinary route and to a lesser extent by biliary route, but mostly as metabolites. In cynomolgus monkeys, the parent drug predominated in plasma with only trace amounts of metabolites detected.

  5. Acyl glucuronide conjugate of CHDI-340246 was not detected in plasma of rats or monkeys.

  6. Overall, the ADME profile of CHDI-340246 was favourable in rats and monkeys for potential evaluation of KMO inhibition in humans.

Acknowledgments

This work was funded by CHDI Foundation (https://chdifoundation.org/) whose sole mission is to accelerate therapeutic development for Huntington's D disease. V. Khetarpal, T. Herbst, I. Munoz-Sanjuan, and C. Dominguez are employees of CHDI Management that supports CHDI Foundation. All studies were conducted by contract research organizations (CROs) under fee-for-service agreements.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Log in via your institution

Log in to Taylor & Francis Online

PDF download + Online access

  • 48 hours access to article PDF & online version
  • Article PDF can be downloaded
  • Article PDF can be printed
USD 65.00 Add to cart

Issue Purchase

  • 30 days online access to complete issue
  • Article PDFs can be downloaded
  • Article PDFs can be printed
USD 897.00 Add to cart

* Local tax will be added as applicable

Related Research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.