Pharmacokinetics and pharmacodynamics of the synthetic cannabinoid, 5F-MDMB-PICA, in male rats

• NCJ Number: 302974
• Journal: Neuropharmacology Volume: 199 Dated: November 2021
• Author(s): Alex J. Krotulski ; Nancy Garibay ; Donna Walther ; Sara E. Walton ; Amanda L.A. Mohr ; Barry K. Logan ; Michael H. Baumann
• Date Published: November 2021
• Grant Number(s): 2017-R2-CX-0021
• Agencies: NIJ-Sponsored
• Publication Type: Research (Applied/Empirical)
• Award: Retrospective Identification of Synthetic Cannabinoids in Forensic Toxicology Casework using Archived High Resolution Mass Spectrometry Data

Annotation

This study had three aims: 1) to develop a validated method for detection of 5F-MDMB-PICA, a popular synthetic cannabinoid associated with analytically confirmed intoxications, and its metabolites in rat plasma, 2) to use the method for investigating pharmacokinetics of 5F-MDMB-PICA in rats, and 3) to relate 5F-MDMB-PICA pharmacokinetics to pharmacodynamic effects.

Abstract

In vitro studies show 5F-MDMB-PICA is a potent cannabinoid-1 receptor (CB1) agonist, but little information is available about in vivo pharmacokinetics and pharmacodynamics. In the current study, 5F-MDMB-PICA and its metabolites were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS), and method validation followed forensic standards. Male Sprague-Dawley rats bearing surgically implanted jugular catheters and subcutaneous (s.c.) temperature transponders received 5F-MDMB-PICA (50, 100, or 200 μg/kg, s.c.) or its vehicle. Blood samples were drawn at 15, 30, 60, 120, 240, and 480 minute post-injection, and plasma was assayed using LC-MS/MS. At each blood draw, body temperature, and catalepsy scores were recorded. Maximum plasma concentrations (Cmax) of 5F-MDMB-PICA rose linearly with increasing dose (1.72–6.20 ng/mL), and plasma half-life (t1/2) ranged from 400 to 1000 min 5F-MDMB-PICA-3,3-dimethylbutanoic acid and 5OH-MDMB-PICA were the only metabolites detected, and plasma concentrations were much lower than the parent drug. 5F-MDMB-PICA induced robust hypothermia and catalepsy-like symptoms that were significantly correlated with concentrations of 5F-MDMB-PICA. Radioligand binding in rat brain membranes revealed 5F-MDMB-PICA displays high affinity for CB1 (IC50 = 2 nM) while metabolites do not. In summary, 5F-MDMB-PICA is a potent CB1 agonist in rats whose pharmacodynamic effects are related to circulating concentrations of the parent drug and not its metabolites. (publisher abstract modified)