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 |
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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: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3171759 |