Electroencephalographic Spectral and Coherence Analysis of Ketamine in Rats: Correlation with Behavioral Effects and Pharmacokinetics

Páleníček, Tomáš; Fujáková, M.; Brunovský, Martin; Balı́ková, Marie; Horáček, Jiří; Gorman, Ingmar; Tylš, Filip; Tislerova, B.; Šóš, P.; Bubeníková-Valešová, Věra; Höschl, Cyril; Krajča, Vladimı́r

doi:10.1159/000321803

Cited by 72 publications

(73 citation statements)

References 157 publications

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“…Three further metabolites of Ket were simultaneously detected (Figures S3 and S4): hydroxyketamine (HK), hydroxynorketamine (HNK), and dehydronorketamine (DHNK). [13] Administration of multiple sub-anaesthetic doses of Ket led to concentration distributions similar to those previously reported, with ah alf-life (t 1/2 )o f2 3min (Figures 2a and S5), which agrees well with values obtained from plasma. [14] Note that aprecise comparison between breath and plasma values would require very frequent plasma sampling, which is difficult or impossible with current methodologies due to volumetric constraints.…”

supporting

confidence: 86%

“…This has been found for the blood-tobrain transport efficiencyo fN K, which is inferior to that of Ket. [13] However,f urther direct comparisons with LCMS experiments on tissues would be needed to confirm this hypothesis.I na ddition, while translating ion intensity into absolute gas-phase concentrations is possible, [18] it is instrument-and compound-dependent. In this study,w er eport on ion intensity,r ather than absolute gas-phase concentrations.…”

Section: Angewandte Communicationsmentioning

confidence: 99%

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Drug Pharmacokinetics Determined by Real‐Time Analysis of Mouse Breath

et al. 2015

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Noninvasive, real-time pharmacokinetic (PK) monitoring of ketamine, propofol, and valproic acid, and their metabolites was achieved in mice, using secondary electrospray ionization and high-resolution mass spectrometry. The PK profile of a drug influences its efficacy and toxicity because it determines exposure time and levels. The antidepressant and anaesthetic ketamine (Ket) and four Ket metabolites were studied in detail and their PK was simultaneously determined following application of different sub-anaesthetic doses of Ket. Bioavailability after oral administration vs. intraperitoneal injection was also investigated. In contrast to conventional studies that require many animals to be sacrificed even for low-resolution PK curves, this novel approach yields real-time PK curves with a hitherto unmatched time resolution (10 s), and none of the animals has to be sacrificed. This thus represents a major step forward not only in animal welfare, but also major cost and time savings.

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supporting

confidence: 86%

Section: Angewandte Communicationsmentioning

confidence: 99%

Drug Pharmacokinetics Determined by Real‐Time Analysis of Mouse Breath

et al. 2015

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“…In order to compare the rate values obtained from the model with known PK data for ketamine in the brain, we applied the PK fitting procedure (equations 1, 2 and 3) to the published PK data from Palenicek et al [36]. This data set corresponds to brain concentration of ketamine after the i.p.…”

Section: Resultsmentioning

confidence: 99%

“…We fitted equations 1, 2 and 3 to the published PK data was obtained from Palenicek et al [36], and it was extracted using the software PlotDigitizer v2.6.6. The rate constants reported in the text were selected by using the higher R 2 criteria.…”

Section: Methodsmentioning

confidence: 99%

A PK–PD model of ketamine-induced high-frequency oscillations

et al. 2015

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Objective Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a High-Frequency Oscillation (HFO) which power is modulated non-linearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PD) of ketamine and the observed HFO power. Approach In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by a high-frequency oscillation (HFO) observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.

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“…However, glutamatergic models showed an increase in the power of gamma wave band after administering ketamine and MK-801, while a discrete decrease in theta and beta band were seen after the administration of MK-801. 28,29 However, no prominent changes were noticed in our patients even after administering multiple antiepileptic drugs before commencing ACTH treatment.…”

Section: Discussionmentioning

confidence: 53%