Skip to main content
Erschienen in: Forensic Toxicology 1/2018

09.10.2017 | Original Article

Metabolic and pharmacokinetic characterization of a new synthetic cannabinoid APINAC in rats

verfasst von: Jungjoong Hwang, Jiho Hwang, Bogonda Ganganna, Insuk Song, Moon Young Heo, Sung-Hoon Ahn, Jongkook Lee

Erschienen in: Forensic Toxicology | Ausgabe 1/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate (APINAC), a new synthetic cannabinoid, was recently isolated from a dietary supplement and identified in our laboratories. The metabolism and pharmacokinetics of APINAC were studied in vitro and in vivo with a rat model.

Methods

APINAC (2.0 μM) was incubated with rat liver microsomes (RLMs) for up to 90 min to determine its phase I metabolic profile. APINAC was also administered to rats at a dose of 5 mg/kg intravenously (i.v.) or 10 mg/kg per os (p.o.). Blood samples were collected at specific time points, and urine samples were also collected for 1 day following APINAC administration. The analyses were conducted by both high- and low-resolution liquid chromatography–tandem mass spectrometry.

Results

Although APINAC was rapidly metabolized by RLMs (t 1/2, 15.2 ± 0.4 min), in vivo pharmacokinetic experiments in rats revealed moderate to long half-lives [11.3 h (i.v.) and 3.8 h (p.o.)]. A total of 22 APINAC metabolites could be detected in the RLMs and rat urine. APINAC was predominantly metabolized via ester hydrolysis to carboxylic acids M1 (with hydroxylation) and M18 (without hydroxylation), representative markers for APINAC intake. Hydroxylation of APINAC, with or without subsequent oxidation and glucuronidation, was observed in the case of the other metabolites.

Conclusions

The diagnosis of illegal APINAC intake can be realized through the detection of several characteristic APINAC metabolites in human urine and/or APINAC itself in blood.
Literatur
1.
Zurück zum Zitat Nutt D, King LA, Saulsbury W, Blakemore C (2007) Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 369:1047–1053CrossRefPubMed Nutt D, King LA, Saulsbury W, Blakemore C (2007) Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 369:1047–1053CrossRefPubMed
2.
Zurück zum Zitat van Amsterdam J, Nutt D, Phillips L, van den Brink W (2015) European rating of drug harms. J Psychopharmacol 29:655–660CrossRefPubMed van Amsterdam J, Nutt D, Phillips L, van den Brink W (2015) European rating of drug harms. J Psychopharmacol 29:655–660CrossRefPubMed
4.
Zurück zum Zitat Babor TF, McRee BG, Kassebaum PA, Grimaldi PL, Ahmed K, Bray J (2007) Screening, brief intervention, and referral to treatment (SBIRT) toward a public health approach to the management of substance abuse. Subst Abuse 28:7–30CrossRef Babor TF, McRee BG, Kassebaum PA, Grimaldi PL, Ahmed K, Bray J (2007) Screening, brief intervention, and referral to treatment (SBIRT) toward a public health approach to the management of substance abuse. Subst Abuse 28:7–30CrossRef
5.
Zurück zum Zitat Higgins ST, Silverman K, Heil SH (eds) (2008) Contingency management in substance abuse treatment. Guilford Press, New York London Higgins ST, Silverman K, Heil SH (eds) (2008) Contingency management in substance abuse treatment. Guilford Press, New York London
7.
Zurück zum Zitat Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V (2013) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 108:534–544CrossRefPubMed Hermanns-Clausen M, Kneisel S, Szabo B, Auwärter V (2013) Acute toxicity due to the confirmed consumption of synthetic cannabinoids: clinical and laboratory findings. Addiction 108:534–544CrossRefPubMed
8.
Zurück zum Zitat Seely KA, Lapoint J, Moran JH, Fattore L (2012) Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 39:234–243CrossRefPubMedPubMedCentral Seely KA, Lapoint J, Moran JH, Fattore L (2012) Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry 39:234–243CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Forrester MB, Kleinschmidt K, Schwarz E, Young A (2012) Synthetic cannabinoid and marijuana exposures reported to poison centers. Hum Exp Toxicol 31:1006–1011CrossRefPubMed Forrester MB, Kleinschmidt K, Schwarz E, Young A (2012) Synthetic cannabinoid and marijuana exposures reported to poison centers. Hum Exp Toxicol 31:1006–1011CrossRefPubMed
10.
Zurück zum Zitat Young AC, Schwarz E, Medina G, Obafemi A, Feng SY, Kane C, Kleinschmidt K (2012) Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am J Emerg Med 30:e1325–e1327CrossRef Young AC, Schwarz E, Medina G, Obafemi A, Feng SY, Kane C, Kleinschmidt K (2012) Cardiotoxicity associated with the synthetic cannabinoid, K9, with laboratory confirmation. Am J Emerg Med 30:e1325–e1327CrossRef
11.
Zurück zum Zitat Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James LP, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH (2012) Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos 40:2174–2184CrossRefPubMedPubMedCentral Chimalakonda KC, Seely KA, Bratton SM, Brents LK, Moran CL, Endres GW, James LP, Hollenberg PF, Prather PL, Radominska-Pandya A, Moran JH (2012) Cytochrome P450-mediated oxidative metabolism of abused synthetic cannabinoids found in K2/Spice: identification of novel cannabinoid receptor ligands. Drug Metab Dispos 40:2174–2184CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Sobolevsky T, Prasolov I, Rodchenkov G (2012) Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. Drug Test Anal 4:745–753CrossRefPubMed Sobolevsky T, Prasolov I, Rodchenkov G (2012) Detection of urinary metabolites of AM-2201 and UR-144, two novel synthetic cannabinoids. Drug Test Anal 4:745–753CrossRefPubMed
13.
Zurück zum Zitat Scheidweiler KB, Jarvis MJ, Huestis MA (2015) Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography–high-resolution tandem mass spectrometry. Anal Bioanal Chem 407:883–897CrossRefPubMed Scheidweiler KB, Jarvis MJ, Huestis MA (2015) Nontargeted SWATH acquisition for identifying 47 synthetic cannabinoid metabolites in human urine by liquid chromatography–high-resolution tandem mass spectrometry. Anal Bioanal Chem 407:883–897CrossRefPubMed
14.
Zurück zum Zitat Uchiyama N, Kawamura M, Kikura-Hanajiri R, Goda Y (2012) Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products. Forensic Toxicol 30:114–125CrossRef Uchiyama N, Kawamura M, Kikura-Hanajiri R, Goda Y (2012) Identification of two new-type synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of five synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer drugs in illegal products. Forensic Toxicol 30:114–125CrossRef
15.
Zurück zum Zitat Drug Enforcement Administration, Department of Justice (2016) Schedules of controlled substances: placement of UR-144, XLR11, and AKB48 into Schedule I. Final rule. Fed Regist 81:29142–29145 Drug Enforcement Administration, Department of Justice (2016) Schedules of controlled substances: placement of UR-144, XLR11, and AKB48 into Schedule I. Final rule. Fed Regist 81:29142–29145
16.
Zurück zum Zitat Lee JH, Park HN, Leem TS, Jeon JH, Cho S, Lee J, Baek SY (2017) Identification of new synthetic cannabinoid analogue APINAC (adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate) with other synthetic cannabinoid MDMB (N)-Bz-F in illegal products. Forensic Toxicol 35:45–55CrossRef Lee JH, Park HN, Leem TS, Jeon JH, Cho S, Lee J, Baek SY (2017) Identification of new synthetic cannabinoid analogue APINAC (adamantan-1-yl 1-pentyl-1H-indazole-3-carboxylate) with other synthetic cannabinoid MDMB (N)-Bz-F in illegal products. Forensic Toxicol 35:45–55CrossRef
17.
Zurück zum Zitat Savchuk S, Appolonova S, Pechnikov A, Rizvanova L, Shestakova K, Tagliaro F (2017) In vivo metabolism of the new synthetic cannabinoid APINAC in rats by GC–MS and LC–QTOF-MS. Forensic Toxicol 35:359–368CrossRef Savchuk S, Appolonova S, Pechnikov A, Rizvanova L, Shestakova K, Tagliaro F (2017) In vivo metabolism of the new synthetic cannabinoid APINAC in rats by GC–MS and LC–QTOF-MS. Forensic Toxicol 35:359–368CrossRef
18.
Zurück zum Zitat Gandhi AS, Zhu M, Pang S, Wohlfarth A, Scheidweiler KB, Liu HF, Huestis MA (2013) First characterization of AKB-48 metabolism, a novel synthetic cannabinoid, using human hepatocytes and high-resolution mass spectrometry. AAPS J 15:1091–1098CrossRefPubMedPubMedCentral Gandhi AS, Zhu M, Pang S, Wohlfarth A, Scheidweiler KB, Liu HF, Huestis MA (2013) First characterization of AKB-48 metabolism, a novel synthetic cannabinoid, using human hepatocytes and high-resolution mass spectrometry. AAPS J 15:1091–1098CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Diao X, Carlier J, Zhu M, Pang S, Kronstrand R, Scheidweiler KB, Huestis MA (2017) In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201). Forensic Toxicol 35:20–32CrossRefPubMed Diao X, Carlier J, Zhu M, Pang S, Kronstrand R, Scheidweiler KB, Huestis MA (2017) In vitro and in vivo human metabolism of a new synthetic cannabinoid NM-2201 (CBL-2201). Forensic Toxicol 35:20–32CrossRefPubMed
20.
Zurück zum Zitat Wohlfarth A, Gandhi AS, Pang S, Zhu M, Scheidweiler KB, Huestis MA (2014) Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry. Anal Bioanal Chem 406:1763–1780CrossRefPubMed Wohlfarth A, Gandhi AS, Pang S, Zhu M, Scheidweiler KB, Huestis MA (2014) Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry. Anal Bioanal Chem 406:1763–1780CrossRefPubMed
21.
Zurück zum Zitat Wintermeyer A, Möller I, Thevis M, Jübner M, Beike J, Rothschild MA, Bender K (2010) In vitro phase I metabolism of the synthetic cannabimimetic JWH-018. Anal Bioanal Chem 398:2141–2153CrossRefPubMed Wintermeyer A, Möller I, Thevis M, Jübner M, Beike J, Rothschild MA, Bender K (2010) In vitro phase I metabolism of the synthetic cannabimimetic JWH-018. Anal Bioanal Chem 398:2141–2153CrossRefPubMed
22.
Zurück zum Zitat Holm NB, Pedersen AJ, Dalsgaard PW, Linnet K (2014) Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry. Drug Test Anal 7:199–206CrossRefPubMed Holm NB, Pedersen AJ, Dalsgaard PW, Linnet K (2014) Metabolites of 5F-AKB-48, a synthetic cannabinoid receptor agonist, identified in human urine and liver microsomal preparations using liquid chromatography high-resolution mass spectrometry. Drug Test Anal 7:199–206CrossRefPubMed
23.
Zurück zum Zitat Vikingsson S, Josefsson M, Green H (2015) Identification of AKB-48 and 5F-AKB-48 metabolites in authentic human urine samples using human liver microsomes and time of flight mass spectrometry. J Anal Toxicol 39:426–435CrossRefPubMed Vikingsson S, Josefsson M, Green H (2015) Identification of AKB-48 and 5F-AKB-48 metabolites in authentic human urine samples using human liver microsomes and time of flight mass spectrometry. J Anal Toxicol 39:426–435CrossRefPubMed
24.
Zurück zum Zitat Castaneto MS, Scheidweiler KB, Gandhi A, Wohlfarth A, Klette KL, Martin TM, Huestis MA (2014) Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens. Drug Test Anal 7:483–493CrossRefPubMedPubMedCentral Castaneto MS, Scheidweiler KB, Gandhi A, Wohlfarth A, Klette KL, Martin TM, Huestis MA (2014) Quantitative urine confirmatory testing for synthetic cannabinoids in randomly collected urine specimens. Drug Test Anal 7:483–493CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Hutter M, Broecker S, Kneisel S, Auwärter V (2012) Identification of the major urinary metabolites in man of seven synthetic cannabinoids of the aminoalkylindole type present as adulterants in ‘herbal mixtures’ using LC–MS/MS techniques. J Mass Spectrom 47:54–65CrossRefPubMed Hutter M, Broecker S, Kneisel S, Auwärter V (2012) Identification of the major urinary metabolites in man of seven synthetic cannabinoids of the aminoalkylindole type present as adulterants in ‘herbal mixtures’ using LC–MS/MS techniques. J Mass Spectrom 47:54–65CrossRefPubMed
Metadaten
Titel
Metabolic and pharmacokinetic characterization of a new synthetic cannabinoid APINAC in rats
verfasst von
Jungjoong Hwang
Jiho Hwang
Bogonda Ganganna
Insuk Song
Moon Young Heo
Sung-Hoon Ahn
Jongkook Lee
Publikationsdatum
09.10.2017
Verlag
Springer Japan
Erschienen in
Forensic Toxicology / Ausgabe 1/2018
Print ISSN: 1860-8965
Elektronische ISSN: 1860-8973
DOI
https://doi.org/10.1007/s11419-017-0387-4

Weitere Artikel der Ausgabe 1/2018

Forensic Toxicology 1/2018 Zur Ausgabe

Neu im Fachgebiet Rechtsmedizin