Targeted Metabolomic Approach for Assessing Human Synthetic Cannabinoid Exposure and Pharmacology
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- 作者：Amy L. Patton ; Kathryn A. Seely ; Krishna C. Chimalakonda ; Johnny P. Tran ; Matthew Trass ; Art Miranda ; William E. Fantegrossi ; Paul D. Kennedy ; Paul Dobrowolski ; Anna Radominska-Pandya ; Keith R. McCain ; Laura P. James ; Gregory W. Endres ; Jeffery H. Moran
- 刊名：Analytical Chemistry
- 出版年：2013
- 出版时间：October 1, 2013
- 年：2013
- 卷：85
- 期：19
- 页码：9390-9399
- 全文大小：729K
- 年卷期：v.85,no.19(October 1, 2013)
- ISSN：1520-6882
文摘
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 (蠅)- and (蠅-1)-monohydroxyl metabolites that retain high affinity for cannabinoid type-1 receptors, exhibit 螖9-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 (蠅-1)-monohydroxyl enantiomers in human metabolism and toxicity. This study uses a chiral liquid chromatography鈥搕andem mass spectroscopy approach (LC鈥揗S/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 r2 = 0.89). Pilot data from human urine samples demonstrate enantiospecific excretion patterns. The (S)-isomer of the JWH-018-(蠅-1)-monohydroxyl metabolite was predominantly excreted (>87%) in human urine as the glucuronic acid conjugate, whereas the relative abundance of the corresponding AM2201-(蠅-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.