Pharmacogenetics of Anesthesia

Aroke, Edwin N.; Dungan, Jennifer R.

doi:10.1097/nnr.0000000000000164

Cited by 10 publications

(5 citation statements)

References 36 publications

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“…Propofol is excreted in the urine after glucuroconjugation of the parent drug (to form the propofol-glucuronide) and sulfo- and glucuroconjugation of the hydroxylated metabolite to form 4-(2,6-diisopropyl-1,4-quinol)-sulfate, 1- or 4-(2,6-diisopropyl-1,4)-glucuronide, respectively. Current evidence suggests that close monitoring is required when administering anesthetics to individuals with the CYP2B6 ∗ 6 allele [ 181 ]. Nevertheless, additional studies are needed to elucidate and characterize polymorphic enzymes in explaining interindividual variations of the glucuronidation metabolic pathway and their pharmacological and toxicological adverse reactions.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Dinis-Oliveira

2018

BioMed Research International

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Propofol is an intravenous short-acting anesthetic widely used to induce and maintain general anesthesia and to provide procedural sedation. The potential for propofol dependency and abuse has been recognized, and several cases of accidental overdose and suicide have emerged, mostly among the health professionals. Different studies have demonstrated an unpredictable interindividual variability of propofol pharmacokinetics and pharmacodynamics with forensic and clinical adverse relevant outcomes (e.g., pronounced respiratory and cardiac depression), namely, due to polymorphisms in the UDP-glucuronosyltransferase and cytochrome P450 isoforms and drugs administered concurrently. In this work the pharmacokinetics of propofol and fospropofol with particular focus on metabolic pathways is fully reviewed. It is concluded that knowing the metabolism of propofol may lead to the development of new clues to help further toxicological and clinical interpretations and to reduce serious adverse reactions such as respiratory failure, metabolic acidosis, rhabdomyolysis, cardiac bradyarrhythmias, hypotension and myocardial failure, anaphylaxis, hypertriglyceridemia, renal failure, hepatomegaly, hepatic steatosis, acute pancreatitis, abuse, and death. Particularly, further studies aiming to characterize polymorphic enzymes involved in the metabolic pathway, the development of additional routine forensic toxicological analysis, and the relatively new field of ‘‘omics” technology, namely, metabolomics, can offer more in explaining the unpredictable interindividual variability.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Dinis-Oliveira

2018

BioMed Research International

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“…Clinical investigations on ketamine and its enantiomers (R)‐ketamine (arketamine) and (S)‐ketamine (esketamine) have mostly focused on its anaesthetic properties 1 . However, recently, ketamine has gained increasing interest in clinical practice due to its anti‐inflammatory, analgesic and antidepressant effects 2 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Langmia

Just

Yamoune

et al. 2022

Brit J Clinical Pharma

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Ketamine and its enantiomer S‐ketamine (esketamine) are known to produce rapid‐onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short‐term use in anaesthesia and analgesia, the experience with ketamine as long‐term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene‐drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug–drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug–drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long‐term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions.

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“…the metabolome) and their changes over time [ 34 ]. Several studies have demonstrated an unpredictable inter-individual variability of ketamine pharmacokinetics and pharmacodynamics [ 35 , 36 ]. Moreover, metabolic substrates and/or inhibitors or inducers of the same cytochrome P450 isoforms (CYP) implicated in ketamine metabolism are administered concurrently and thus important clinical and forensic consequences are expected.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and metabolomics of ketamine: a toxicological approach

Dinis-Oliveira

2017

Forensic Sciences Research

116

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Ketamine is a phencyclidine derivative and a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor for which glutamate is the full agonist. It produces a functional dissociation between the thalamocortical and limbic systems, a state that has been termed as dissociative anaesthesia. Considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile has been reported. This review aims to discuss pharmacokinetics of ketamine, namely focusing on all major and minor, active and inactive metabolites. Both ketamine optical isomers undergo hepatic biotransformation through the cytochrome P450, specially involving the isoenzymes 3A4 and 2B6. It is first N-demethylated to active metabolite norketamine. Different minor pathways have been described, namely hydroxylation of the cyclohexanone ring of ketamine and norketamine, and further conjugation with glucuronic acid to increase renal excretion. More recently, metabolomics data evidenced the alteration of several biological pathways after ketamine administration such as glycolysis, tricarboxylic acid cycle, amino acids metabolism and mitochondrial β-oxidation of fatty acids. It is expected that knowing the metabolism and metabolomics of ketamine may provide further insights aiming to better characterize ketamine from a clinical and forensic perspective.

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Pharmacogenetics of Anesthesia

Cited by 10 publications

References 36 publications

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

Metabolism and metabolomics of ketamine: a toxicological approach

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