Can toxicokinetics of (synthetic) cannabinoids in pigs after pulmonary administration be upscaled to humans by allometric techniques?
Graphical abstract
Introduction
Synthetic cannabinoids (SC) were originally synthesized in the context of structure–activity relationship studies [1], [2], [3], but have increasingly been consumed as a substitute of cannabis to elude the narcotics law. Especially during the last six years, the number of newly emerged SCs has significantly increased in Europe [4]. SC often exhibit higher affinities to the cannabinoid receptor (CB) 2 as well as CB1. This receptor is responsible for the psychoactive, but also antiemetic and analgesic effects [5], explaining the usefulness in the treatment of i.e. nausea during cancer treatment or cachexia in the context of an acquired immune deficiency syndrome. Beyond that, even higher potencies have been observed as compared to Δ9-tetrahydrocannabinol (THC) [6], [7], [8], resulting in unpredictable psychoactive effects, ending up in intoxications with life-threatening conditions or even death [5], [9]. Regarding these issues, SC have become a tremendous public health concern and are gaining increasing relevance in clinical and forensic toxicology. Unlike THC, whose toxicokinetic (TK) and toxicodynamic properties have extensively been examined [10], [11], [12], [13], [14], [15], [16], [17], neither preclinical safety-data nor TK data from controlled studies are available for SC. However, explicit TK data are indispensable when interpreting analytical data from individuals who are either impaired or have overdosed following drug use (i.e. time of ingestion and plasma concentrations related to clinical observations), but in addition and especially if precise expert opinion in forensic cases is required (i.e. driving under the influence of drugs). Only few SC TK data have been obtained so far, which are based on in-vitro or few systematic animal studies, single case reports, or self-experiments with only one or two participants [18], [19], [20]. Recently, Toennes et al. [21] conducted a systematic human study in order to assess adverse effects and TK of JWH-018 after inhalation. However, this database obtained in these pioneer studies has to be supplemented for a even more comprehensive characterization of the TK properties of this drug class.
A pilot study to establish a pig model suitable for cannabinoid TK studies after intravenous (i.v.) administration of THC, 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210), and 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) [22], [23], [24], [25] and allowing for prediction of human data applying a mathematical approach and allometric scaling techniques [23] has provided first knowledge concerning that issue. In this study, a three compartment model as well as an allometric scaling exponent of 0.75 on each TK parameter described the data best [23].
Nevertheless, the most common route of SC consumption is smoking [6]. Furthermore, inhalation of vaporized cannabinoids via electronic cigarettes has also been reported [26]. Thus, an administration set-up reflecting authentic user habits should be established using the former developed pig model in order to supplement the data obtained after i.v. administration. Therefore, the aim of the present study was to elucidate the TK of THC as well as the two SC JWH-210 and RCS-4 after standardized pulmonary administration to ventilated anesthetized pigs using an ultrasonic-assisted nebulizer [27]. For this purpose, the concentration-time profiles should be determined in a first step. For evaluation of the bioavailability, the data obtained from the pulmonary administration experiments should be compared to those determined in the i.v. study. In a second step, the concentration-time profiles should be modeled and assessed whether the THC model can predict published data in humans by upscaling the THC pig model to humans using allometric techniques. In a third step, simulations of different human dosing scenarios should be performed for JWH-210 and RCS-4. At last, the main urinary metabolites should be identified by liquid-chromatography high-resolution mass spectrometry (LC-HR-MS/MS). Results should be compared with those detected after i.v. administration and finally correlated to human data.
Section snippets
Chemicals and reagents
Glacial acetic acid per analysis (p.a.), isopropanol p.a., acetone Supra Solv, methanol Supra Solv, formic acid EMSURE, and di-potassium hydrogen phosphate EMSURE were obtained from Merck (Darmstadt, Germany). High pressure (HP) LC grade water was purchased from VWR-International (Darmstadt, Germany) and ethanol p.a. and HPLC grade acetonitrile from Sigma-Aldrich (Steinheim, Germany). Ammonium formate (analytical grade) was obtained from Fluka (Neu-Ulm, Germany), methanolic solution of THC
Serum concentration-time profiles
Following pulmonary administration of 200 µg/kg BW to male domestic pigs, Cmax were reached 10–15 min (tmax) after the beginning of nebulization and amounted to 66 ± 36 ng/mL for THC, 41 ± 11 ng/mL for JWH-210, and 34 ± 8.9 ng/mL for RCS-4. Concentrations rapidly declined within the first hour, indicating a distribution into tissues. After 60 min, mean concentrations of 14 ± 5.7 ng/mL for THC, 12 ± 6.9 ng/mL for JWH-210, and 6.5 ± 2.2 ng/mL for RCS-4 were observed. Subsequently, a slower
Pulmonary administration
To establish an authentic consumption scenario, we present a novel standardized experimental method of pulmonary drug administration by using a nebulizer operating in an inspiration-triggered mode. Unlike a permanent nebulization, the triggered mode allowed for successive nebulization (<0.2 mL/min) of the drug solution synchronized with each inspiratory phase resulting in a 12 min administration process of the whole dose. Applying this protocol, a set-up similar to that used for systematic PK
Acknowledgements
The authors thank Benjamin Peters and the staff of the Institute for Clinical & Experimental Surgery at Saarland University for their support and help during the study as well as the Saarland University for the research grant (Anschubfinanzierung von Forschungsprojekten, 61-cl/Anschub 2017/bew-Schäfer).
Conflict of interest
There are no financial or other relations that could lead to a conflict of interest.
References (64)
- et al.
Design, synthesis and pharmacology of cannabimimetic indoles
Bioorg. Med. Chem. Lett.
(1994) - et al.
Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: steric and electronic effects of 4- and 8-halogenated naphthoyl substituents
Bioorg. Med. Chem.
(2012) - et al.
Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications
Drug Alcohol. Depend.
(2014) - et al.
Pharmacokinetics of delta9-tetrahydrocannabinol in dogs
J. Pharm. Sci.
(1977) - et al.
A vapourized Δ9-tetrahydrocannabinol (Δ9-THC) delivery system. part II: Comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents
J. Pharmacol. Toxicol. Methods
(2014) - et al.
Pharmacokinetic properties of the synthetic cannabinoid JWH-018 and of its metabolites in serum after inhalation
J. Pharm. Biomed. Anal.
(2017) - et al.
Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology
Toxicol. Lett.
(2016) - et al.
Orbitrap technology for comprehensive metabolite-based liquid chromatographic–high resolution-tandem mass spectrometric urine drug screening – exemplified for cardiovascular drugs
Anal. Chim. Acta
(2015) - et al.
Disposition and bioavailability of various formulations of tetrahydrocannabinol in the rhesus monkey
J. Pharm. Sci.
(1985) - et al.
Validation of Large White Pig as an animal model for the study of cannabinoids metabolism: application to the study of THC distribution in tissues
Forensic Sci. Int.
(2006)
Evaluation of a vaporizing device (Volcano®) for the pulmonary administration of tetrahydrocannabinol
J. Pharm. Sci.
Sensitive and rapid quantification of the cannabinoid receptor agonist naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in human serum by liquid chromatography-tandem mass spectrometry
J. Chromatogr. B Anal. Technol. Biomed. Life Sci.
Development and pharmacokinetic characterization of pulmonal and intravenous delta-9-tetrahydrocannabinol (THC) in humans
J. Pharm. Sci.
Simultaneous quantification of free and glucuronidated cannabinoids in human urine by liquid chromatography tandem mass spectrometry
Clin. Chim. Acta
Cannabimimetic indoles, pyrroles, and indenes: structure–activity relationships and receptor interactions. The cannabinoid receptors
Synthetic cannabinoids: pharmacology, behavioral effects, and abuse potential
Curr. Addic. Rep.
‘Spice’ and other herbal blends: harmless incense or cannabinoid designer drugs?
J. Mass Spectrom.
A fatal case involving several synthetic cannabinoids
Toxichem. Krimtech.
Pharmacokinetics of delta9-tetrahydrocannabinol in rabbits following single or multiple intravenous doses
Drug Metab. Dispos.
Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana
J. Anal. Toxicol.
Single dose kinetics of deuterium labelled Δ1-tetrahydrocannabinol in heavy and light cannabis users
Biol. Mass Spectrom.
Clinical effects and plasma levels of Δ9-Tetrahydrocannabinol (Δ9-THC) in heavy and light users of cannabis
Psychopharmacology (Berl).
Tolerance and disposition of tetrahydrocannabinol in man
J. Pharmacol. Exp. Ther.
Effect of intrapulmonary tetrahydrocannabinol administration in humans
J. Psychopharmacol.
Synthetic cannabinoids pharmacokinetics and detection methods in biological matrices
Drug Metab. Rev.
Recent developments in urinalysis of metabolites of new psychoactive substances using LC–MS
Bioanalysis
New psychoactive substances: an overview on recent publications on their toxicodynamics and toxicokinetics
Arch. Toxicol.
Simultaneous LC-MS/MS determination of JWH-210, RCS-4, delta9-tetrahydrocannabinol, and their main metabolites in pig and human serum, whole blood, and urine for comparing pharmacokinetic data
Anal. Bioanal. Chem.
Metabolic patterns of JWH-210, RCS-4, and THC in pig urine elucidated using LC-HR-MS/MS: Do they reflect patterns in humans?
Drug Test Anal.
Distribution of synthetic cannabinoids JWH-210, RCS-4 and Δ 9-tetrahydrocannabinol after intravenous administration to pigs
Curr. Neuropharmacol.
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