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

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.

Metabolic profiling of synthetic cannabinoid 5F‐ADB by human liver microsome incubations and urine samples using high‐resolution mass spectrometry

“…Similar dehalogenation and further oxidation reactions have been reported as major metabolic pathways for 5F‐AMB, THJ‐2201, 5F‐AB‐PINACA, AM‐2201, XLR‐11, 5F‐PB‐22, 5F‐CUMYL‐PICA, 5F‐AKB‐48, and 5F‐MDMB‐PICA …”

“…All the metabolites identified using HLMs were observed in authentic human urine samples, except for M14. Similarly, for CUMYL‐PICA, 5F‐CUMYL‐PICA, and NNEI N ‐dealkylation metabolite was reported in vitro, but not detected in urine samples . We also detected 5F‐ADB as the parent drug in 12 of the 30 authentic urine samples.…”

In vitro metabolism of the synthetic cannabinoids PX‐1, PX‐2, and PX‐3 by high‐resolution mass spectrometry and their clearance rates in human liver microsomes

“…However, similarities in diagnostic ions were observed. Two common fragments, m/z 144 and m/z 232, observed in PX‐1 and similar PICA SCs are characteristic of the indole core and fluoropentyl tail . The fragments m/z 145, 233, and 213 were observed in the elucidation of PX‐2 and other PINACA compounds and are characteristic of the indazole core and fluoropentyl tail .…”

Phase I metabolism of the recently emerged synthetic cannabinoid CUMYL‐PEGACLONE and detection in human urine samples

“…Phase I metabolism studies revealed that CUMYL‐PEGACLONE is an extensively metabolized SC. In contrast to former cumyl‐derivatives, the main in vivo metabolite M20 was unexpectedly hydroxylated at the γ ‐carbolinone core whereas former analogs were mainly hydroxylated at the pentyl side chain . The metabolites M20 and M09 were identified as sensitive and specific urinary markers to proof uptake of this highly prevalent substance.…”