Can toxicokinetics of (synthetic) cannabinoids in pigs after pulmonary administration be upscaled to humans by allometric techniques?

Autor: Schaefer N; Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saar, Germany. Electronic address: nadine.schaefer@uks.eu., Wojtyniak JG; Clinical Pharmacy, Saarland University, D-66123 Saarbruecken, Germany., Kroell AK; Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saar, Germany., Koerbel C; Institute for Clinical & Experimental Surgery, Saarland University, Building 65/66, D-66421 Homburg, Saar, Germany., Laschke MW; Institute for Clinical & Experimental Surgery, Saarland University, Building 65/66, D-66421 Homburg, Saar, Germany., Lehr T; Clinical Pharmacy, Saarland University, D-66123 Saarbruecken, Germany., Menger MD; Institute for Clinical & Experimental Surgery, Saarland University, Building 65/66, D-66421 Homburg, Saar, Germany., Maurer HH; Department of Experimental and Clinical Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Building 46, D-66421 Homburg, Saar, Germany., Meyer MR; Department of Experimental and Clinical Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Building 46, D-66421 Homburg, Saar, Germany., Schmidt PH; Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saar, Germany.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2018 Sep; Vol. 155, pp. 403-418. Date of Electronic Publication: 2018 Jul 24.
DOI: 10.1016/j.bcp.2018.07.029
Abstrakt: Being advertised and distributed as attractive substitutes of cannabis, synthetic cannabinoids (SC) are gaining increasing relevance in forensic and clinical toxicology. As no data from controlled human studies are available, SC are sold and consumed without the knowledge of their toxicokinetic (TK) and toxicodynamic properties. Hence, animal models coupled with mathematical approaches should be used to ascertain those properties. Therefore, a controlled pig TK study allowing for extrapolation to human data was performed. For this purpose, eleven pigs received a single pulmonary dose of 200 µg/kg body weight each of Δ9-tetrahydrocannabinol (THC), 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210) as well as 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) via an ultrasonic nebulizer. Blood and urine samples were repeatedly drawn over 8 h. Serum-concentration-time profiles of the parent compounds were determined using LC-MS/MS. Urine specimens were analyzed by LC-HR-MS/MS in order to elucidate the main metabolites. Maximum serum concentrations were reached 10-15 min after 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. The serum-concentration-time profiles of THC, JWH-210, and RCS-4 were best described by three-compartment models with first order absorption and elimination processes. Absorption from the lungs to serum was modeled by first-order processes. The determination of the bioavailability yielded 23.0%, 24.2%, and 45.7% for THC, JWH-210, and RCS-4, respectively. Furthermore, the developed THC model was upscaled to humans using allometric scaling techniques. A successful prediction of human concentration-time profiles could be done. Also the metabolic patterns were in good agreement with human data. In conclusion, these findings are the first reported regarding the TK properties of SC after pulmonary administration to pigs. The presented method of TK serves as an appropriate predictor of human TK of cannabinoids.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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