Abstract
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.
Highlights
Synthetic cannabinoid receptor 1 (CB1) agonists comprise a large and growing class of recreationally used novel psychoactive substances
The molecular structures of these compounds are regularly altered in an attempt to evade drug detection and legislation [10], and users of synthetic cannabinoids are frequently exposed to novel substances with unknown pharmacokinetic and pharmacodynamic properties
Clearance of CUMYL-PICA and 5F-CUMYL-PICA was rapid in rat and human liver microsome incubations (Fig. 3a–d; Table 1)
Summary
Synthetic cannabinoid receptor 1 (CB1) agonists comprise a large and growing class of recreationally used novel psychoactive substances. The molecular structures of these compounds are regularly altered in an attempt to evade drug detection and legislation [10], and users of synthetic cannabinoids are frequently exposed to novel substances with unknown pharmacokinetic and pharmacodynamic properties. Two such novel synthetic cannabinoids are CUMYLPICA [1-pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] and its fluorinated analogue 5F-CUMYL-PICA [1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3carboxamide]. These synthetic cannabinoids are a,adimethylbenzyl analogues of SDB-006 and 5F-SDB-006, which are in turn analogues of SDB-001 (APICA) and STS-135 (Fig. 1). They are structurally related to a Forensic Toxicol (2017) 35:333–347
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