Role of transporters and enzymes in metabolism and distribution of 4 chlorokynurenine and metabolites

Patel, Waseema, Shankar, Ravi, Smith, Mark, Snodgrass, Ralph, Pirmohamed, Munir ORCID: 0000-0002-7534-7266, Jorgensen, Andrea, Alfirevic, Ana and Dickens, David ORCID: 0000-0001-8295-0752 (2023) Role of transporters and enzymes in metabolism and distribution of 4 chlorokynurenine and metabolites. [Preprint]

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Abstract

4-chlorokynurenine (4-Cl-KYN) is in clinical development for potential CNS indications. We have 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 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 had 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:	Preprint
Uncontrolled Keywords:	31 Biological Sciences, 32 Biomedical and Clinical Sciences, 34 Chemical Sciences, 3105 Genetics, 3205 Medical Biochemistry and Metabolomics, 3214 Pharmacology and Pharmaceutical Sciences, 5.1 Pharmaceuticals
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:	19 Jul 2023 08:38
Last Modified:	01 Sep 2024 11:49
DOI:	10.1101/2023.07.14.548888
Related URLs:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3171759