Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects
نویسندگان
چکیده
Background The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well inactive dehydronorketamine. Oral administration favors formation 2,6-hydroxynorketamines via extensive presystemic metabolism. authors hypothesized that plasma exposure relative psychoactive greater prolonged-release tablets than it ketamine. Methods Pharmacokinetics infusion (5.0 mg) single-dose administrations 10, 20, 40, 80 mg prolonged-released were evaluated in 15 healthy white human subjects by means a controlled, ascending-dose study. stereoisomers metabolites quantified serum urine validated tandem mass-spectrometric assays noncompartmental pharmacokinetic analysis. Results After 40 tablets, mean ± SD area under concentrations–time curve ratios for 2,6-hydroxynorketamine/ketamine 18 11 (S-stereoisomers) 30 16 (R-stereoisomers) compared 1.7 0.8 3.1 1.4 (both P < 0.001). 10 20 R-ratios even greater. distribution volumes at steady state S- R-ketamine 6.6 2.2 5.6 2.1 l/kg, terminal half-lives 5.2 3.4 6.1 h, metabolic clearances 1,620 380 1,530 ml/min, respectively. Bioavailability was 8 (S-isomer) 19 10% (R-isomer) half-life 4 h. About 7% dose renally excreted 17% R-stereoisomers. Conclusions Prolonged-release generate high systemic might therefore be an efficient safer pharmaceutical dosage form treatment patients with chronic neuropathic pain infusion. Editor’s Perspective What We Already Know about This Topic Article Tells Us That Is New
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ژورنال
عنوان ژورنال: Anesthesiology
سال: 2021
ISSN: ['0003-3022', '1528-1175']
DOI: https://doi.org/10.1097/aln.0000000000003829