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

Dinis-Oliveira, Ricardo Jorge

doi:10.1155/2018/6852857

Cited by 72 publications

(53 citation statements)

References 179 publications

(195 reference statements)

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“…Search methodology was performed as described in previous publications on the metabolism and metabolomics of other drugs [5,[18][19][20][21][22][23][24][25][26][27]. Briefly, an English, Spanish, Portuguese and German extensive literature search was carried out in PubMed (U.S. National Library of Medicine) without a limiting period to identify relevant articles on pharmacoki-netics and pharmacodynamics of mescaline, related known metabolizing enzymes and metabolites, and effects of mescaline and peyote.…”

Section: Methodsologymentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions

Dinis-Oliveira

Pereira

Silva

2019

CMP

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Background: Mescaline (3,4,5-trimethoxyphenethylamine), mainly found in the Peyote cactus (Lophophora williamsii), is one of the oldest known hallucinogenic agents that influence human and animal behavior, but its psychoactive mechanisms remain poorly understood. Objective: This article aims to fully review pharmacokinetics and pharmacodynamics of mescaline, focusing on the in vivo and in vitro metabolic profile of the drug and its implications for the variability of response. Methods: Mescaline pharmacokinetic and pharmacodynamic aspects were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Biological effects of other compounds found in peyote were also reviewed. Results: Although its illicit administration is less common, in comparison with cocaine and Cannabis, it has been extensively described in adolescents and young adults, and licit consumption often occurs in religious and therapeutic rituals practiced by the Native American Church. Its pharmacodynamic mechanisms of action are primarily attributed to the interaction with the serotonergic 5-HT2A-C receptors, and therefore clinical effects are similar to those elicited by other psychoactive substances, such as lysergic acid diethylamide (LSD) and psilocybin, which include euphoria, hallucinations, depersonalization and psychoses. Moreover, as a phenethylamine derivative, signs and symptoms are consistent with a sympathomimetic effect. Mescaline is mainly metabolized into trimethoxyphenylacetic acid by oxidative deamination but several minor metabolites with possible clinical and forensic repercussions have also been reported. Conclusion: Most reports concerning mescaline were presented in a complete absence of exposure confirmation, since toxicological analysis is not widely available. Addiction and dependence are practically absent and it is clear that most intoxications appear to be mild and are unlikely to produce lifethreatening symptoms, which favors the contemporary interest in the therapeutic potential of the drugs of the class.

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Section: Methodsologymentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions

Dinis-Oliveira

Pereira

Silva

2019

CMP

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“…The incubation time used was 3 min to mimic the PR duration of action after bolus dose according to the drug PK/PD data. 36 After that, 170 μL of the supernatant was measured by HPLC–tandem mass spectrometry (HPLC–MS/MS) to determine the PR unbound fraction (fu prop ) according to a detailed protocol. Additionally, the bound PR fraction (fb prop ) was assessed as a difference of the fu 0 and fu prop values according to the equation where fu 0 is the unbound fraction (fu) of PR when the SA concentration is zero.…”

Section: Methodsmentioning

confidence: 99%

Novel Approach for Characterizing Propofol Binding Affinities to Serum Albumins from Different Species

Shityakov

Fischer

et al. 2020

ACS Omega

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The interaction between the main carrier (serum albumin, SA) of endogenous and exogenous compounds in the bloodstream of different species (human, bovine, canine, rat, rabbit, and sheep) and a general anesthetic agent (propofol, PR) was investigated using an experimental technique (high-performance liquid chromatography) and computational methods (molecular docking, molecular dynamics, sequence, and phylogenetic analyses). The obtained results revealed the differences in the PR binding affinity to various homologous forms of this protein with reliable statistics ( R 2 = 0.9 and p -value < 0.005), correlating with the evolutionary relationships among SAs from different species. Additionally, the protein conformational changes (root-mean-square deviation ≈ 1.0 Å) and amino acid conservation of binding sites in protein domains were detected, contributing to the SA–PR binding modes. Overall, the outcomes from this study might provide a novel methodology to assess protein–ligand interactions and to gain some interesting insights into drug pharmacokinetics and pharmacodynamics to explain its variations among different species.

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“…Rapid clearance and awakening after a bolus of propofol occurs in humans as well as mice. 10 , 37 However, the behavioral, cognitive, neurophysiological and synaptic plasticity effects of propofol, ketamine, and brexanolone and other anesthetic agents have been reported to persist in rodents and humans substantially longer than would be anticipated by their pharmacokinetic and pharmacodynamic profiles alone. 2 , 4 , 11 , 17 , 26 , 27 , 33 , 34 , 38 , 39 , 40 , 41 For example, in their review, Browne and Lucki 41 observed that “the majority of studies indicate that the FST remains sensitive to the protracted effects of ketamine up to 1 week after a single injection.” Thus, the rapid clearance of propofol is unlikely to explain the lack of influence on an FST at 24 hours.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Propofol on a Forced Swim Test in Mice at 24 Hours

Daniel

et al. 2020

Current Therapeutic Research

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Background There are few rapidly acting treatments for acute suicidality or treatment-resistant depression. Propofol (2,6-diisopropylphenol) is an intravenous anesthetic agent used in outpatient settings. It is a gamma-aminobutyric acid type A agonist and has affinity at the N-methyl-D-aspartate receptor. Elevation in mood and sociality in humans has been observed following propofol-induced anesthesia. Other authors reported an open-label study of repeated dosing of propofol in treatment-resistant depression in which several patients experienced sustained improvement. Recently, we reported that in a rodent model of despair, a forced swim test, 45 minutes after administration of 50 mg/kg propofol, immobility time was significantly reduced. Objective The objective of the experiment was to determine whether the antidepressant-like effects of a single dose of propofol in mice are sustained for 24 hours. Methods The time spent immobile during a forced swim test 24 hours after intraperitoneal administration of a single dose of propofol 50 mg/kg or 0.9% saline was evaluated in 24 adult male mice (C57/BL6). Immobility time was quantified and evaluated with a custom video analysis software program. Results Propofol-treated mice were immobile for a mean (SEM) time of 115 (13) seconds, whereas saline-treated mice were immobile for a mean (SEM) time of 94 (14) seconds. A 2-tailed unpaired t test found no significant difference between the treatment groups ( t = 1.07, df = 22; P = 0.30). Conclusions Twenty-four hours after intraperitoneal administration, the effect of propofol on immobility time was not statistically significantly different from vehicle. However, given our previous report of at least a short-term benefit of propofol on struggling time in the forced swim time and an encouraging pilot study in humans with treatment-resistant depression, further evaluation of propofol's antidepressant potential may be warranted.

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

Cited by 72 publications

References 179 publications

Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions

Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions

Novel Approach for Characterizing Propofol Binding Affinities to Serum Albumins from Different Species

The Effect of Propofol on a Forced Swim Test in Mice at 24 Hours

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