Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects.
Background: The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration...
| Publicado en: | Anesthesiology Vol. 135; no. 2; pp. 326 - 340 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Lippincott Williams & Wilkins
Aug2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=151616953&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 151616953 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00033022 1V8 jtl: Anesthesiology issn: 00033022 maglogo: N pubinfo: dt: Aug2021 vid: 135 iid: 2 pid: 433 pub: Lippincott Williams & Wilkins place: Baltimore, Maryland artinfo: ui: 151616953 151616953 NLM34019627 151616953 10.1097/ALN.0000000000003829 NLM34019627 151616953 ppf: 326 ppct: 14 formats: tig: atl: Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects. aug: au: Hasan, Mahmoud Modess, Christiane Roustom, Tarek Dokter, Anne Grube, Markus Link, Andreas Rey, Hélène Adler, Stefanie Meissner, Konrad Siegmund, Werner affil: Department of Clinical Pharmacology, University Medicine Greifswald, Greifswald, Germany. sug: subj: Analgesics Pharmacokinetics Ketamine Metabolism Ketamine Pharmacokinetics Analgesics Metabolism Female Ketamine Administration and Dosage Analgesics Administration and Dosage Research Subjects Delayed-Action Preparations Adult Male Human Young Adult Administration, Oral Reference Values Comparative Studies Multicenter Studies Evaluation Research Validation Studies Adult: 19-44 years Female Male ab: Background: The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine.Methods: Pharmacokinetics of ketamine after intravenous infusion (5.0 mg) and single-dose administrations of 10, 20, 40, and 80 mg prolonged-released tablets were evaluated in 15 healthy white human subjects by means of a controlled, ascending-dose study. The stereoisomers of ketamine and metabolites were quantified in serum and urine by validated tandem mass-spectrometric assays and evaluated by noncompartmental pharmacokinetic analysis.Results: After 40 mg prolonged-release tablets, the mean ± SD area under the concentrations-time curve ratios for 2,6-hydroxynorketamine/ketamine were 18 ± 11 (S-stereoisomers) and 30 ± 16 (R-stereoisomers) compared to 1.7 ± 0.8 and 3.1 ± 1.4 and after intravenous infusion (both P < 0.001). After 10 and 20 mg tablets, the R-ratios were even greater. The distribution volumes at steady state of S- and R-ketamine were 6.6 ± 2.2 and 5.6 ± 2.1 l/kg, terminal half-lives 5.2 ± 3.4 and 6.1 ± 3.1 h, and metabolic clearances 1,620 ± 380 and 1,530 ± 380 ml/min, respectively. Bioavailability of the 40 mg tablets was 15 ± 8 (S-isomer) and 19 ± 10% (R-isomer) and terminal half-life 11 ± 4 and 10 ± 4 h. About 7% of the dose was renally excreted as S-stereoisomers and 17% as R-stereoisomers.Conclusions: Prolonged-release ketamine tablets generate a high systemic exposure to 2,6-hydroxynorketamines and might therefore be an efficient and safer pharmaceutical dosage form for treatment of patients with chronic neuropathic pain compared to intravenous infusion.Editor’s Perspective: pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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