A Review of the Metabolism and Relevance to Form and Formulation of Ketamine
Bibliographic record
Abstract
Introduction Ketamine is a phenylcyclohexylamine derivative comprising a racemic mixture of S- and R-ketamine that possesses anesthetic, analgesic, anti-inflammatory, and antidepressant activity. Oral (including extended release [PO]), intravenous (IV) sublingual (SL), transmucosal (TM), intranasal (IN), intramuscular (IM), rectal (PR), and subcutaneous (SC) formulations have been developed since its commercialization in 1970. Objectives To review and understand the impact of different forms and formulations on the pharmacokinetics of ketamine. Methods The extant literature on ketamine metabolism and formulations was reviewed and discussed. Results IV (racemic) ketamine (KET) has been shown to improve depressed mood within 4 hours with maximal effect at 24 hours. KET is a chiral molecule with two optimal isomers, R- and S-KET. KET is stereoselectively metabolized by CYP2B6 and CYP3A4 initially via nitrogen demethylation to active metabolite, norketamine (NK); there is no interconversion between R- and S-KET. NK is further metabolized to hydroxynorketamine (HNK) by CYP3A4 and CYP3A5; and dehydronorketamine (DHNK) by CYP2B6. Additional metabolic pathways exist including a direct enantioselective hydroxylation of KET to 6-hydroxyketamine (HK). Bioavailablity is greatest (100%) with the IV racemic KET formulation, but as low as 8% for oral S-KET due to extensive first-pass metabolism; the KET: NK ratio is a measure of first pass metabolism. NK plasma levels are higher with oral S-KET than KET as a result of local intestinal metabolism effects. Additionally, greater plasma concentrations are noted with IV bolus doses of S-KET vs. racemic KET or R-KET. S-KET possesses a longer elimination half-life than racemic KET due to inhibition by R-KET. KET is primarily renally eliminated and twice as fast in children vs. adults. Conclusions Complex interactions are reported between ketamine form (racemic/enantiomer), formulation, dose, and route of administration that impact on clinical variables and thus, outcome. Disclosure of Interest None Declared
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".