Does a carboxamide moiety alter the toxicokinetics of synthetic cannabinoids? A study after pulmonary and intravenous administration of cumyl-5F-P7AICA to pigs

Synthetic cannabinoids (SCs) are consumed as an alternative to cannabis. Novel compounds are developed by minor modifications in their chemical structure, e.g. insertion of a carboxamide moiety as a linker, which can potentially lead to altered toxicokinetics (TK). Knowledge on the TK data of SCs, especially structural modified substances, is scarce. Hence, interpretation of toxicological results is challenging. Therefore, the aim of the present study was to evaluate the TK of cumyl-5F-P7AICA in a pig model, which was shown to be suitable for TK studies of SCs. A 200 µg/kg body weight dose of cumyl-5F-P7AICA was administered intravenously (n = 6) or inhalatively (n = 10) via an ultrasonic nebulizer to pigs. Blood specimens were repeatedly drawn over 6 h and the concentrations of cumyl-5F-P7AICA as well as its N-pentanoic acid (NPA) metabolite were determined using a fully validated LC-MS/MS method. Based on the concentration-time profiles, a population TK analysis yielded a three-compartment model for the TK of cumyl-5F-P7AICA, whilst a two-compartment model described the NPA best. The incorporation of transit compartments accounts for the time delay between the appearance of cumyl-5F-P7AICA and NPA in serum. Finally, the model was upscaled to humans using allometric scaling. In comparison to older SCs, a higher volume of distribution was determined for cumyl-5F-P7AICA. No further relevant differences of the TK properties were observed. Insertion of a carboxamide moiety into the chemical structure of SCs does not appear to have only minor influence on the TK.