Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers

Pharmacol Res Perspect. 2021 Apr;9(2):e00741. doi: 10.1002/prp2.741.


The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.

Keywords: epilepsy; glutamat; kynurenic acid; migraine; stroke.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blood Flow Velocity / drug effects
  • Cerebrovascular Circulation / drug effects*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Epilepsy / drug therapy
  • Female
  • Healthy Volunteers
  • Humans
  • Infusions, Intravenous
  • Kynurenine / administration & dosage
  • Kynurenine / adverse effects*
  • Kynurenine / pharmacokinetics
  • Male
  • Pilot Projects
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects*
  • Prodrugs / pharmacokinetics
  • Rats
  • Stroke / drug therapy
  • Young Adult


  • Prodrugs
  • Kynurenine