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Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes

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Abstract

Synthetic cannabinoids, a new class of psychoactive substances, are potent agonists of cannabinoid receptors, which mimic the psychoactive effects of the principal psychoactive component of cannabis, ∆9-tetrahydrocannabinol. Despite governmental scheduling as illicit drugs, new synthetic cannabinoids are being produced. The abuse of synthetic cannabinoids with several drugs containing different chemical groups has resulted in large numbers of poisonings. This has increased the urgency for forensic and public health laboratories to identify the metabolites of synthetic cannabinoids and apply this knowledge to the development of analytical methods and for toxicity prediction. It is necessary to determine whether synthetic cannabinoids are involved in drug-metabolizing enzyme-mediated drug–drug interactions. This review describes the metabolic pathways of 13 prevalent synthetic cannabinoids and various drug-metabolizing enzymes responsible for their metabolism, including cytochrome P450 (CYP), UDP-glucuronosyltransferases (UGTs), and carboxylesterases. The inhibitory effects of synthetic cannabinoids on CYP and UGT activities are also reviewed to predict the potential of synthetic cannabinoids for drug–drug interactions. The drug-metabolizing enzymes responsible for metabolism of synthetic cannabinoids should be characterized and the effects of synthetic cannabinoids on CYP and UGT activities should be determined to predict the pharmacokinetics of synthetic cannabinoids and synthetic cannabinoid-induced drug–drug interactions in the clinic.

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Acknowledgements

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT) (NRF-2015M3A9E1028325).

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  1. BK21 PLUS Team for Creative Leader Program for Pharmacomics-Based Future Pharmacy and Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, 14662, Republic of Korea

    Tae Yeon Kong, Dong Kyun Kim & Hye Suk Lee

  2. Department of Pharmacology, College of Medicine, Dongguk University, Gyeongju, 38066, Republic of Korea

    Ju-Hyun Kim

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  1. Tae Yeon Kong
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Correspondence to Hye Suk Lee.

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Kong, T.Y., Kim, JH., Kim, D.K. et al. Synthetic cannabinoids are substrates and inhibitors of multiple drug-metabolizing enzymes. Arch. Pharm. Res. 41, 691–710 (2018). https://doi.org/10.1007/s12272-018-1055-x

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