Abstract
New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC–MS/MS. The concentration–time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration–time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.
Highlights
A large and increasing number of new psychoactive substances (NPS) with similar effects as compared to classical drugs of abuse have been released in Europe for about aFor a few years one of the most popular New synthetic opioids (NSOs) U-47700 has emerged on the drugs of abuse market (World Health Organization 2016)
The aims of the present study were to (i) elucidate TK data of U-47700, (ii) examine whether domestic pigs can be used for the prediction of human TK of this substance and tramadol and (iii) evaluate a multiple species allometric scaling approach
At the end of the experiment, 8 h after administration, concentrations ( Clast) of 0.8 ± 0.3 ng/mL U-47700 and 6.6 ± 2.3 ng/mL tramadol were still determined in serum samples
Summary
For a few years one of the most popular NSO U-47700 has emerged on the drugs of abuse market (World Health Organization 2016). It was initially sold via the internet as a legal alternative to common opioid drugs, such as heroin or morphine (Mohr et al 2016; Rohrig et al 2017). Unlike tramadol, whose toxicokinetic (TK) properties have extensively been elucidated using different animal models or controlled human studies with different routes of administration (Murthy et al 2000; Vullo et al 2014; Evangelista Vaz et al 2018), preclinical safety data of U-47700 are still lacking except for data from multiple metabolism studies and one animal study in rats (Solimini et al 2018; Truver et al 2020). Standardized and controlled animal studies remain the only tool for the assessment of TK properties
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