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                            Library & Multimedia
 Plasma pharmacokinetics and pharmacodynamic effects of the 2-benzylbenzimidazole synthetic opioid, isotonitazene, in male rats
NCJ Number
              306067
Journal

*PSYCHOPHARMACOLOGY* Volume: 240 Dated: 2023 Pages: 185-198
Author(s)
          Sara E. Walton;
                        Alex J. Krotulski;
                        Grant C. Glatfelter;
                        Donna Walther;
                        Barry K. Logan;
                        Michael H. Baumann
Date Published

2023
Length
              14 pages
Annotation
              This study investigated the pharmacokinetics of isotonitazene in rats, and related pharmacokinetic parameters to pharmacodynamic effects.
Abstract
              Isotonitazene and its metabolites were identified and quantified by liquid chromatography tandem quadrupole mass spectrometry (LC-QQQ-MS). Male Sprague–Dawley rats with jugular catheters and subcutaneous (s.c.) temperature transponders received isotonitazene (3, 10, 30 μg/kg, s.c.) or its vehicle. Blood samples were drawn at 15-, 30-, 60-, 120-, and 240-min post-injection, and plasma was assayed using LC-QQQ-MS. At each blood draw, body temperature, catalepsy scores, and hot plate latencies were recorded. Maximum plasma concentrations of isotonitazene rose in parallel with increasing dose (range 0.2–9.8 ng/mL) and half-life ranged from 23.4 to 63.3 min. The metabolites 4′-hydroxy nitazene and N-desethyl isotonitazene were detected, and plasma concentrations were below the limit of quantitation (0.5 ng/mL) but above the limit of detection (0.1 ng/mL). Isotonitazene produced antinociception (ED50 = 4.22 μg/kg), catalepsy-like symptoms (ED50 = 8.68 μg/kg), and hypothermia (only at 30 μg/kg) that were significantly correlated with concentrations of isotonitazene. Radioligand binding in rat brain tissue revealed that isotonitazene displays nM affinity for MOR (Ki = 15.8 nM), while the N-desethyl metabolite shows even greater affinity (Ki = 2.2 nM). In summary, isotonitazene is a potent MOR agonist whose pharmacodynamic effects are related to circulating concentrations of the parent drug. The high potency of isotonitazene portends substantial risk to users who are exposed to the drug. (Published abstract provided)
      
  
          Additional Details
Grant Number(s)
        2020-DQ-BX-0007


  
  
        
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        NIJ-Sponsored


  
  
        
  Publication Type
        Research (Applied/Empirical)


  
  
        
  Award
        Real-Time Sample-Mining and Data-Mining Approaches for the Discovery of Novel Psychoactive Substances (NPS)
    
  
  
Date Published: January 1, 2023
    
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