Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology.
Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs.
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saarland, Germany. Electronic address: nadine.schaefer@uks.eu.
Nadine
N
Schaefer
Clinical Pharmacy, Saarland University, D-66123 Saarbruecken, Germany.
Jan-Georg
JG
Wojtyniak
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saarland, Germany.
Mattias
M
Kettner
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saarland, Germany.
Julia
J
Schlote
Institute for Clinical & Experimental Surgery, Saarland University, Building 65/66, D-66421 Homburg, Saarland, Germany.
Matthias W
MW
Laschke
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saarland, Germany.
Andreas H
AH
Ewald
Clinical Pharmacy, Saarland University, D-66123 Saarbruecken, Germany.
Thorsten
T
Lehr
Institute for Clinical & Experimental Surgery, Saarland University, Building 65/66, D-66421 Homburg, Saarland, Germany.
Michael D
MD
Menger
Department of Experimental and Clinical Toxicology, Saarland University, Building 46, D-66421 Homburg, Saarland, Germany.
Hans H
HH
Maurer
Institute of Legal Medicine, Saarland University, Building 80.2, D-66421 Homburg, Saarland, Germany.
Peter H
PH
Schmidt
D000818:Animals; D002186:Cannabinoids / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D013759:Dronabinol / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D053593:Forensic Toxicology / Q000379:methods*; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D023421:Models, Animal; D008954:Models, Biological; D009281:Naphthalenes / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013045:Species Specificity; D013552:Swine; D053719:Tandem Mass Spectrometry
C000613875:2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone; C582338:4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone; D002186:Cannabinoids; D007211:Indoles; D009281:Naphthalenes; D013759:Dronabinol
LC–MS/MS; Pigs; Population pharmacokinetic modeling; Prediction of human pharmacokinetics; Synthetic cannabinoids; Tetrahydrocannabinol