Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101).

Patel, Waseema, Shankar, Ravi G, Smith, Mark A, Snodgrass, H Ralph, Pirmohamed, Munir ORCID: 0000-0002-7534-7266, Jorgensen, Andrea L ORCID: 0000-0002-6977-9337, Alfirevic, Ana and Dickens, David ORCID: 0000-0001-8295-0752 (2024) Role of Transporters and Enzymes in Metabolism and Distribution of 4-Chlorokynurenine (AV-101). Molecular pharmaceutics, 21 (2). pp. 550-563.

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Official URL: http://dx.doi.org/10.1021/acs.molpharmaceut.3c0070...

Abstract

4-Chlorokynurenine (4-Cl-KYN, AV-101) is a prodrug of a NMDA receptor antagonist and is in clinical development for potential CNS indications. We sought to further understand the distribution and metabolism of 4-Cl-KYN, as this information might provide a strategy to enhance the clinical development of this drug. We used excretion studies in rats, in vitro transporter assays, and pharmacogenetic analysis of clinical trial data to determine how 4-Cl-KYN and metabolites are distributed. Our data indicated that a novel acetylated metabolite (N-acetyl-4-Cl-KYN) did not affect the uptake of 4-Cl-KYN across the blood-brain barrier via LAT1. 4-Cl-KYN and its metabolites were found to be renally excreted in rodents. In addition, we found that N-acetyl-4-Cl-KYN inhibited renal and hepatic transporters involved in excretion. Thus, this metabolite has the potential to limit the excretion of a range of compounds. Our pharmacogenetic analysis found that a SNP in N-acetyltransferase 8 (NAT8, rs13538) was linked to levels of N-acetyl-4-Cl-KYN relative to 4-Cl-KYN found in the plasma and that a SNP in SLC7A5 (rs28582913) was associated with the plasma levels of the active metabolite, 7-Cl-KYNA. Thus, we have a pharmacogenetics-based association for plasma drug level that could aid in the drug development of 4-Cl-KYN and have investigated the interaction of a novel metabolite with drug transporters.

Item Type:	Article
Uncontrolled Keywords:	Animals, Rats, Kynurenic Acid, Kynurenine, Analgesics, Neuroprotective Agents
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	29 Jan 2024 09:52
Last Modified:	10 Feb 2024 02:03
DOI:	10.1021/acs.molpharmaceut.3c00700
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178052