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L\u2010kynurenine (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\u2010label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150\u00a0\u00b5g\/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5\u00a0mg\/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\u2010tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23\u00a0\u00b1\u00a01.12\u00a0\u00b5g\/mL (after 50\u00a0\u00b5g\/kg), 4.04\u00a0\u00b1\u00a01.1\u00a0\u00b5g\/mL (after 100\u00a0\u00b5g\/kg), and 5.25\u00a0\u00b1\u00a01.01\u00a0\u00b5g\/mL (after 150\u00a0\u00b5g\/kg) (<jats:italic>p<\/jats:italic>\u00a0\u2264\u00a00.001). 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\u2010in\u2010human study of LKYN showed that LKYN was safe and well\u2010tolerated after intravenous infusion up to 5\u00a0mg\/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\u2010back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.<\/jats:p>","DOI":"10.1002\/prp2.741","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T06:06:13Z","timestamp":1615183573000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-9665","authenticated-orcid":false,"given":"Mohammad Al\u2010Mahdi","family":"Al\u2010Karagholi","sequence":"first","affiliation":[{"name":"Danish Headache Center Department of Neurology University of Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob M\u00f8ller","family":"Hansen","sequence":"additional","affiliation":[{"name":"Danish Headache Center Department 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