{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:40:16Z","timestamp":1763707216483,"version":"3.45.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Ketamine is a significant class of antidepressant drugs, and the pharmacokinetic and pharmacodynamic characteristics of its enantiomers exhibit differences. Among them, intravenous infusion of (R)-ketamine can effectively alleviate depressive symptoms in patients, offering the advantages of prolonged duration of action and minimal side effects. The extensive preclinical pharmacokinetic (PK) studies of (R)-ketamine were conducted to support its further development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study investigated the preclinical pharmacokinetic behavior of (R)-ketamine across different dose groups through single- and multiple-dose pharmacokinetic studies in rats and dogs, along with tissue distribution studies in Sprague-Dawley (SD) rats.\n                      <jats:italic>In vitro<\/jats:italic>\n                      metabolism study using microsomes from mice, rats, dogs, monkeys, and humans were conducted to evaluate metabolic stability and obtain metabolite profiles. The excretion studies in rats (7.5\u00a0mg\/kg dose group) were performed to elucidate the primary elimination pathways of (R)-ketamine. The allometric scaling approach was employed to predict human plasma total clearance based on preclinical data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>(R)-ketamine exhibits nonlinear pharmacokinetics in SD rats and Beagle dogs, with plasma exposure increasing disproportionately to dose after both single and multiple intravenous administrations. The highest tissue exposure to (R)-Ketamine was found in the fat and kidney of the rats. The (R)-ketamine concentration ratio of brain\/plasma was 2.25 for the rats, indicating effective blood-brain barrier penetration and significant brain distribution of (R)-ketamine. (R)-ketamine undergoes rapid metabolism in liver microsomes from mice, rats, dogs, monkeys and humans. The predominant metabolite identified in human, monkey and mice liver microsomes was (R)-norketamine and demethylated and mono-oxidized metabolites in rats and dogs. (R)-ketamine is primarily excreted via bile, accounting for 3.613% of the dose within 72\u00a0h, significantly higher than in feces (0.327%) or urine (0.030%). The main elimination pathway may be metabolic elimination, and eventually excreted in the form of metabolites. The predicted human plasma total clearance of 29.93\u00a0mL\/min\/kg is close to reported value.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The preclinical pharmacokinetic characteristics of (R)-ketamine injection have been thoroughly investigated, and these findings can provide valuable information for predicting the first-in-human dose and designing Phase I clinical trials for (R)-ketamine injection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1699304","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:31:39Z","timestamp":1763706699000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical pharmacokinetic characterization of (R)-ketamine injection, a novel antidepressant glutamatergic agent"],"prefix":"10.3389","volume":"16","author":[{"given":"Rui","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongchao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingjie","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1101\/500959","article-title":"Rapamycin, an immunosuppressant and mtorc1 inhibitor, triples the antidepressant response rate of ketamine at 2 weeks following treatment: a double-blind, placebo-controlled, cross-over, randomized clinical trial","author":"Abdallah","year":"2018","journal-title":"BioRxiv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.jad.2019.11.028","article-title":"Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression","volume":"263","author":"Acevedo-Diaz","year":"2020","journal-title":"J. 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