Experimental versus theoretical log D<sub>7.4</sub>, pK<sub>a</sub> and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Manchester, Kieran R.; Maskell, Peter; Waters, Laura J.

doi:10.1002/dta.2387

Cited by 19 publications

(15 citation statements)

References 68 publications

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“…Dialysed buffer from each well was tested for protein contamination using BCA protein assay reagent to determine whether membranes had been compromised. Percentage drug bound and fraction unbound were calculated as follows [ 115 ]:

where Pl = Analyte/IS ratio determined in plasma side…”

Section: Methodsmentioning

confidence: 99%

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

et al. 2021

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In vitro pharmacokinetic studies were conducted on enantiomer pairs of twelve valinate or tert-leucinate indole and indazole-3-carboxamide synthetic cannabinoid receptor agonists (SCRAs) detected on the illicit drug market to investigate their physicochemical parameters and structure-metabolism relationships (SMRs). Experimentally derived Log D7.4 ranged from 2.81 (AB-FUBINACA) to 4.95 (MDMB-4en-PINACA) and all SCRAs tested were highly protein bound, ranging from 88.9 ± 0.49% ((R)-4F-MDMB-BINACA) to 99.5 ± 0.08% ((S)-MDMB-FUBINACA). Most tested SCRAs were cleared rapidly in vitro in pooled human liver microsomes (pHLM) and pooled cryopreserved human hepatocytes (pHHeps). Intrinsic clearance (CLint) ranged from 13.7 ± 4.06 ((R)-AB-FUBINACA) to 2944 ± 95.9 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHLM, and from 110 ± 34.5 ((S)-AB-FUBINACA) to 3216 ± 607 mL min−1 kg−1 ((S)-AMB-FUBINACA) in pHHeps. Predicted Human in vivo hepatic clearance (CLH) ranged from 0.34 ± 0.09 ((S)-AB-FUBINACA) to 17.79 ± 0.20 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHLM and 1.39 ± 0.27 ((S)-MDMB-FUBINACA) to 18.25 ± 0.12 mL min−1 kg−1 ((S)-5F-AMB-PINACA) in pHHeps. Valinate and tert-leucinate indole and indazole-3-carboxamide SCRAs are often rapidly metabolised in vitro but are highly protein bound in vivo and therefore predicted in vivo CLH is much slower than CLint. This is likely to give rise to longer detection windows of these substances and their metabolites in urine, possibly as a result of accumulation of parent drug in lipid-rich tissues, with redistribution into the circulatory system and subsequent metabolism.

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where Pl = Analyte/IS ratio determined in plasma side…”

Section: Methodsmentioning

confidence: 99%

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

et al. 2021

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“…Flubromazepam was first identified in a sample of capsules analysed by a German university forensic institute in March 2013 [ 69 , 70 , 72 , 73 ]. There are several anecdotal reports from psychonauts fora which describe it as “ of extreme duration, with effects for larger doses reaching up to three days ” [ 52 , 54 ].…”

Section: Resultsmentioning

confidence: 99%

“…In research investigating its distribution in the plasma and brain of mice tranquillising and anticonvulsive properties were reported [ 124 - 126 ]. It is a full γ- GABA A receptor positive allosteric modulator [ 73 , 126 , 127 ]. 3-hydroxyphenazepam appears to be pharmacologically active with some 5- to 10-fold higher potency than diazepam, probably due to the bromine atom in the molecule [ 128 ].…”

Section: Resultsmentioning

confidence: 99%

‘New/Designer Benzodiazepines’: An Analysis of the Literature and Psychonauts’ Trip Reports

Orsolini

Corkery

Chiappini

et al. 2020

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Background: NPS belonging to the benzodiazepine (BZD) class, e.g., ‘legal/designer BZDs’/‘research chemicals’, have recently emerged on the drug (mainly online/virtual) market. Objective: Whilst certain NPS belonging to the BZD class possess pharmacological profiles similar to controlled pharmaceutical BZDs, clinical and pharmacological profiles of current emerging BZDs are still not well-described. Therefore, there is a need to increase clinicians’/public health knowledge/awareness, to incentive harm reduction strategies. Method: A comprehensive overview was carried out by using the EMCDDA/EDND database regularly monitored by our research team, by specifically looking at the ‘new BZDs’ so far notified. Furthermore, given the limitation of peer-reviewed data published so far, a nonparticipant multilingual qualitative netnographic study was conducted to obtain further clinical/pharmacological/toxicological data, including psychonauts’ online trip reports. Results: First designer BZDs appeared as NPS around 2007. So far, 29 designer BZDs have been notified to the EMCDDA, being some of them extremely powerful, also at lower dosages. They are sold as tablets/powder/pellets/capsules/blotters/liquids, at very affordable prices, and variably administered. Some are also sold on the illicit drugmarket as counterfeit forms of traditional BZDs or as either adulterants or diluents in heroin or other synthetic opioids/cannabinoids. Nowadays, there is no guarantee of the quality of designer BZDs composition/purification and, hence, most NPS consumers may be inadvertently exposed to unsafe and harmful compounds. Conclusions: Given the limited information on their pharmacology/toxicity, variations in dosage, onset of effects, combination of substances, potency, and general patient or individual variability, the concomitant use of these substances with other drugs entails several and unpredictable risks.

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“…To the best of the authors’ knowledge, the blood/plasma ratio for etizolam is not available in the literature. However, based on other benzodiazepines (blood/plasma ratio 0.5–0.8 14 ) and the high plasma protein binding of etizolam (93% 15 ), it would be expected that etizolam would have a blood/plasma ratio similar to other benzodiazepines. This would mean that clinical blood concentrations of etizolam would be expected to be slightly lower than the etizolam concentrations observed in plasma.…”

Section: Resultsmentioning

confidence: 99%

Femoral blood concentrations of the designer benzodiazepine etizolam in post-mortem cases

et al. 2020

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Etizolam is a thienodiazepine that although licensed for clinical usage in Japan, India and South Korea is commonly abused and detected in post-mortem cases around the world. To date, there are limited data in the literature to allow for the interpretation of blood concentrations of etizolam in post-mortem cases. A liquid chromatography with tandem mass spectrometry method was used to quantitate etizolam concentrations in 28 post-mortem cases where etizolam was detected. The median concentration of etizolam in femoral blood was 8.5 ng/mL (range 1.0–172.0 ng/mL; n = 24); in antemortem plasma, the etizolam concentration range was 4–44 ng/mL ( n = 4). The mean age of the individuals abusing etizolam was 38.5 ± 8.4 years (median 39 years), with the majority being male (86%). In all of the cases, multiple drugs were detected, with the most common being pregabalin (61%) followed by morphine/heroin (54%), diazepam (54%) and benzoylecgonine (21%), illustrating the increasing problem of poly-substance use in drug abusers. The cause of death in the cases in which etizolam was detected was multi-drug toxicity in 87.5% of the cases, with 12.5% unrelated to drug use (hangings and blunt-force trauma). These data will further help forensic practitioners with the interpretation of post-mortem etizolam concentrations.

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Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Cited by 19 publications

References 68 publications

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

‘New/Designer Benzodiazepines’: An Analysis of the Literature and Psychonauts’ Trip Reports

Femoral blood concentrations of the designer benzodiazepine etizolam in post-mortem cases

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Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Cited by 19 publications

References 68 publications

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

A Systematic Study of the In Vitro Pharmacokinetics and Estimated Human In Vivo Clearance of Indole and Indazole-3-Carboxamide Synthetic Cannabinoid Receptor Agonists Detected on the Illicit Drug Market

‘New/Designer Benzodiazepines’: An Analysis of the Literature and Psychonauts’ Trip Reports

Femoral blood concentrations of the designer benzodiazepine etizolam in post-mortem cases

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Product

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Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances