Targeted Metabolomic Approach for Assessing Human Synthetic Cannabinoid Exposure and Pharmacology

• Published in: Analytical chemistry (Washington) Vol. 85; no. 19; pp. 9390 - 9399
• Main Authors: Patton, Amy L, Seely, Kathryn A, Chimalakonda, Krishna C, Tran, Johnny P, Trass, Matthew, Miranda, Art, Fantegrossi, William E, Kennedy, Paul D, Dobrowolski, Paul, Radominska-Pandya, Anna, McCain, Keith R, James, Laura P, Endres, Gregory W, Moran, Jeffery H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-10-2013
• Subjects: Analytical chemistry; Chemical compounds; Chromatography; Chromatography, Liquid; Correlation analysis; Enantiomers; Excretion; Human; Humans; Indoles - metabolism; Indoles - pharmacokinetics; Indoles - urine; Mass spectrometry; Metabolism; Metabolites; Metabolomics; Molecular Structure; Naphthalenes - metabolism; Naphthalenes - pharmacokinetics; Naphthalenes - urine; Pharmacology; Solid Phase Extraction; Tandem Mass Spectrometry; Tissue Distribution; Toxicity; Urine
• ISSN: 0003-2700; 1520-6882
• DOI: 10.1021/ac4024704

Designer synthetic cannabinoids like JWH-018 and AM2201 have unique clinical toxicity. Cytochrome-P450-mediated metabolism of each leads to the generation of pharmacologically active (ω)- and (ω-1)-monohydroxyl metabolites that retain high affinity for cannabinoid type-1 receptors, exhibit Δ9-THC-like effects in rodents, and are conjugated with glucuronic acid prior to excretion in human urine. Previous studies have not measured the contribution of the specific (ω-1)-monohydroxyl enantiomers in human metabolism and toxicity. This study uses a chiral liquid chromatography–tandem mass spectroscopy approach (LC–MS/MS) to quantify each specific enantiomer and other nonchiral, human metabolites of JWH-018 and AM2201 in human urine. The accuracy (average % RE = 18.6) and reproducibility (average CV = 15.8%) of the method resulted in low-level quantification (average LLQ = 0.99 ng/mL) of each metabolite. Comparisons with a previously validated nonchiral method showed strong correlation between the two approaches (average r 2 = 0.89). Pilot data from human urine samples demonstrate enantiospecific excretion patterns. The (S)-isomer of the JWH-018-(ω-1)-monohydroxyl metabolite was predominantly excreted (>87%) in human urine as the glucuronic acid conjugate, whereas the relative abundance of the corresponding AM2201-(ω-1)-metabolite was low (<5%) and did not demonstrate enantiospecificity (approximate 50:50 ratio of each enantiomer). The new chiral method provides a comprehensive, targeted metabolomic approach for studying the human metabolism of JWH-018 and AM2201. Preliminary evaluations of specific enantiomeric contributions support the use of this approach in future studies designed to understand the pharmacokinetic properties of JWH-018 and/or AM2201.