1 research outputs found
Role of Transporters and Enzymes in Metabolism and Distribution of 4‑Chlorokynurenine (AV-101)
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