Metabolic profiling of new synthetic cannabinoids AMB and 5F‐AMB by human hepatocyte and liver microsome incubations and high‐resolution mass spectrometry

Andersson, Maria; Diao, Xingxing; Wohlfarth, Ariane; Scheidweiler, Karl B.; Huestis, Marilyn A.

doi:10.1002/rcm.7538

Cited by 59 publications

(78 citation statements)

References 32 publications

(86 reference statements)

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“…A thorough understanding of these processes is important for determining drug toxicology and for identifying these compounds in biological matrices where they are likely extensively metabolized [13–15]. A precise understanding of metabolic pathways is necessary, because closely structurally related synthetic cannabinoids can produce identical metabolites, which can increase the difficulty of forensic identification of a unique compound [13, 15]. In addition, some synthetic cannabinoid metabolites retain cannabinoid receptor efficacy and therefore may be relevant to the overall pharmacological profile following drug administration [16, 17].…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

et al. 2017

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CUMYL-PICA [1-pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] and 5F-CUMYL-PICA [1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] are recently identified recreationally used/abused synthetic cannabinoids, but have uncharacterized pharmacokinetic profiles and metabolic processes. This study characterized clearance and metabolism of these compounds by human and rat liver microsomes and hepatocytes, and then compared these parameters with in vivo rat plasma and urine sampling. It also evaluated hypothermia, a characteristic cannabimimetic effect. Incubation of CUMYL-PICA and 5F-CUMYL-PICA with rat and human liver microsomes suggested rapid metabolic clearance, but in vivo metabolism was prolonged, such that parent compounds remained detectable in rat plasma 24 h post-dosing. At 3 mg/kg (intraperitoneally), both compounds produced moderate hypothermic effects. Twenty-eight metabolites were tentatively identified for CUMYL-PICA and, coincidentally, 28 metabolites for 5F-CUMYL-PICA, primarily consisting of phase I oxidative transformations and phase II glucuronidation. The primary metabolic pathways for both compounds resulted in the formation of identical metabolites following terminal hydroxylation or dealkylation of the N-pentyl chain for CUMYL-PICA or of the 5-fluoropentyl chain for 5F-CUMYL-PICA. These data provide evidence that in vivo elimination of CUMYL-PICA, 5F-CUMYL-PICA and other synthetic cannabinoids is delayed compared to in vitro modeling, possibly due to sequestration into adipose tissue. Additionally, the present data underscore the need for careful selection of metabolites as analytical targets to distinguish between closely related synthetic cannabinoids in forensic settings.

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Section: Introductionmentioning

confidence: 99%

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

et al. 2017

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“…However, drivers taking indazole carboxamide SCs frequently showed rapid recovery within an hour. It has been reported that 5F-AMB is quickly hydrolyzed by hepatic esterase [20], while 5F-AB-PINACA is more slowly metabolized to various products [21]. The rapid recovery seen in this class of SC remains mysterious.…”

Section: Lineage and Timeline Of Scmentioning

confidence: 99%

Motor vehicle collisions caused by the ‘super-strength’ synthetic cannabinoids, MAM-2201, 5F-PB-22, 5F-AB-PINACA, 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014

Kaneko

2017

Forensic Toxicol

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From 2012 to 2014 in Japan, 214 cases of motor vehicle collisions were attributed to the use of illegal drugs. In 93 out of 96 investigated cases, the causative agents were a variety of synthetic cannabinoids (SCs). These SCs can be classified into three groups according to the lineage of the chemical structures: (1) naphthoyl indoles, such as MAM-2201, (2) quinolinyl ester indoles, such as 5F-PB-22, and (3) indazole carboxamides, such as 5F-AB-PINACA, 5F-AMB, and 5F-ADB. These SCs became available sequentially with increasing cannabinoid CB1 agonist potencies and reached a nationwide outbreak in the summer of 2014. They caused acute intoxication with impaired consciousness, anterograde amnesia (impaired memory), catalepsy with muscle rigidity, tachycardia, and vomiting or drooling soon after smoking. Drivers who had abused one of these SCs might unexpectedly experience the acute intoxication that caused uncontrolled driving. These SCs were generally difficult to detect from body fluid samples. It is thought that the highly lipophilic SCs disappear from the blood via rapid degradation by liver enzymes and selective accumulation into adipose tissues. Thus, much effort should be directed to the development of fast and sensitive chemical detection of the drug usage.

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“…To date, all investigated SCs are extensively metabolized in humans and are predominantly excreted as metabolites in urine [6, 16, 22, 23], complicating detection, as metabolites are initially unknown. Knowledge of human metabolism is essential for verifying NM-2201 consumption since urine testing is routine for workplace, clinical and forensic testing.…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)

et al. 2016

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In 2014, NM-2201 (CBL-2201), a novel synthetic cannabinoid (SC), was detected by Russian and United States laboratories. It was already added to the scheduled drugs list in Japan, Sweden and Germany. Unfortunately, no human metabolism data are currently available, making it challenging to confirm its intake because all previous investigated SCs were extensively metabolized. The present study aims to recommend appropriate marker metabolites by investigating NM-2201 metabolism in human hepatocytes and confirm the results in authentic human urine specimens. For the metabolic stability assay, 1 μM NM-2201 was incubated in human liver microsomes (HLMs) for up to 1 h; for metabolite profiling, 10 μM of NM-2201 was incubated in human hepatocytes for 3 h. Two authentic urine specimens from NM-2201 positive cases were analyzed after β-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was achieved with high-resolution mass spectrometry via information-dependent acquisition. NM-2201 was quickly metabolized in HLMs with an 8.0 min half-life. In human hepatocyte incubation samples, a total of thirteen NM-2201 metabolites were identified, generated mainly from ester hydrolysis and further hydroxylation, oxidative defluorination and subsequent glucuronidation. M13 (5-fluoro PB-22 3-carboxyindole) was the major metabolite. In the urine specimens, the parent drug NM-2201 was not detected; M13 was the predominant metabolite after β-glucuronidase hydrolysis. Therefore, based on our study, we recommend the M13 as a suitable urinary marker metabolite for confirming NM-2201 and/or 5F-PB-22 intake.

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Metabolic profiling of new synthetic cannabinoids AMB and 5F‐AMB by human hepatocyte and liver microsome incubations and high‐resolution mass spectrometry

Cited by 59 publications

References 32 publications

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

Motor vehicle collisions caused by the ‘super-strength’ synthetic cannabinoids, MAM-2201, 5F-PB-22, 5F-AB-PINACA, 5F-AMB and 5F-ADB in Japan experienced from 2012 to 2014

In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201)

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