Date of Award

2024

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Sue M Ford

Second Advisor

Gail Cooper

Third Advisor

Sabesan Yoganathan

Abstract

Metonitazene and isotonitazene are two benzimidazole opioids that are contributing to the opioid crisis nationwide. Limited pharmacokinetic data has been published on these nitazene compounds, therefore this study sought to determine if these two structurally similar opioids would have comparable half-lives and clearance utilizing in vitro and in vivo models. Using the data determined in the pharmacokinetic study, and by testing human postmortem cases, this study aimed to inform interpretation of these drugs detected in human casework. Sample analysis for all aspects of the study was performed utilizing LC/MS/MS. In vitro pharmacokinetics of both drugs were examined using a human liver microsomes (HLM) model. Drug solutions at 2.5 ug/mL were incubated with HLM at 1 mg protein/mL. Metonitazene and isotonitazene showed identical rates of metabolism in this model when comparing both mean half-lives (22.6 and 21.9 min) and intrinsic clearance rates (36.5 and 37.2 mL min-1 kg-1) respectively. These half-lives were both significantly shorter than the in vivo study. Sprague Dawley rats were administered a single dose of drug intravenously at 2.5 µg/kg or intraperitoneally at 25 µg/kg. Blood and urine were collected over six hours, and brain and liver were dissected. Metonitazene (88.5 min IV and 117.5 min IP) exhibited a shorter half-life compared to isotonitazene (44.7 min IV and 56.4 min IP) in both administrations. The mean calculated volume of distribution for isotonitazene was higher than metonitazene, 59.6 mL and 37.3 mL respectively, which likely contributed to the longer half-life. In rat urine samples, two metabolites were detected. In human postmortem cases, blood levels for isotonitazene in ten cases, ranged from 0.11 – 12.0 ng/mL and metonitazene in six cases ranged from 0.10 – 1.5 ng/mL. Metonitazene was more likely to be detected in urine. All four metabolites tested were detected in human samples, therefore species differences were exhibited as compared to rats. It has been proven from in vivo studies that despite their structural similarities, metonitazene and isotonitazene show significant differences in clearance from the body. Nitazenes continue to emerge on the illicit market, and this study provides information on how this class of drugs behaves in the body.

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