Probenecid Increases the Concentration of 7-Chlorokynurenic Acid Derived from the Prodrug 4-Chlorokynurenine within the Prefrontal Cortex


Patel, Waseema, Rimmer, Lara, Smith, Martin, Moss, Lucie, Smith, Mark A, Snodgrass, H Ralph, Pirmohamed, Munir ORCID: 0000-0002-7534-7266, Alfirevic, Ana ORCID: 0000-0002-2801-9817 and Dickens, David ORCID: 0000-0001-8295-0752 (2021) Probenecid Increases the Concentration of 7-Chlorokynurenic Acid Derived from the Prodrug 4-Chlorokynurenine within the Prefrontal Cortex. MOLECULAR PHARMACEUTICS, 18 (1). pp. 113-123.

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Abstract

Recent advances in the understanding of depression have led to increasing interest in ketamine and the role that <i>N</i>-methyl-d-aspartate (NMDA) receptor inhibition plays in depression. l-4-Chlorokynurenine (4-Cl-KYN, AV-101), a prodrug, has shown promise as an antidepressant in preclinical studies, but this promise has not been realized in recent clinical trials. We sought to determine if transporters in the CNS could be playing a role in this clinical response. We used radiolabeled uptake assays and microdialysis studies to determine how 4-Cl-KYN and its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA), cross the blood-brain barrier (BBB) to access the brain and its extracellular fluid compartment. Our data indicates that 4-Cl-KYN crosses the blood-brain barrier via the amino acid transporter LAT1 (<i>SLC</i>7<i>A</i>5) after which the 7-Cl-KYNA metabolite leaves the brain extracellular fluid via probenecid-sensitive organic anion transporters OAT1/3 (<i>SLC</i>22<i>A</i>6 and <i>SLC</i>22<i>A</i>8) and MRP4 (<i>ABCC</i>4). Microdialysis studies further validated our in vitro data, indicating that probenecid may be used to boost the bioavailability of 7-Cl-KYNA. Indeed, we found that coadministration of 4-Cl-KYN with probenecid caused a dose-dependent increase by as much as an 885-fold increase in 7-Cl-KYNA concentration in the prefrontal cortex. In summary, our data show that 4-Cl-KYN crosses the BBB using LAT1, while its active metabolite, 7-Cl-KYNA, is rapidly transported out of the brain via OAT1/3 and MRP4. We also identify a hitherto unreported mechanism by which the brain extracellular concentration of 7-Cl-KYNA may be increased to produce significant boosting of the drug concentration at its site of action that could potentially lead to an increased therapeutic effect.

Item Type: Article
Uncontrolled Keywords: LAT1, l-4-chlorokynurenine, 7-chlorokynurenic acid, probenecid, transporters, MRP4
Depositing User: Symplectic Admin
Date Deposited: 12 Jan 2021 10:43
Last Modified: 18 Jan 2023 23:05
DOI: 10.1021/acs.molpharmaceut.0c00727
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3111918
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