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Cannabinoids interaction with membrane transporters - in silico study

Due to the trend of global legalization of medical cannabis, it is expected that there will be an increase in potential drug-drug interactions (DDIs) between active constituents of cannabis-based products and conventional medications used in the treatment of a variety of health conditions. Because DDIs can lead to serious adverse events, drug regulators require that each investigational drug being evaluated for DDI potential at the level of metabolic enzymes and membrane transporters (MT), as these mediate many biological effects of xenobiotics and play an important role in the pharmacokinetics and resistance of small molecule drugs. [1, 2] The aim of this in silico study was to investigate the interaction potential of different phytocannabinoids from the tetrahydrocannabinol group and several newly synthesized derivatives from the same group (n=14) with ATP-binding cassette (ABC) and solute-carrier(SLC) transporters. ADMET Predictor® Transporters Module (Simulations Plus Inc., USA) consisting of substrate/non-substrate and inhibitor/non-inhibitor classifications and Km regression models, was used to evaluate cannabinoid interaction with Pgp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, and BSE transporters. [3] The results of the study showed that the majority of the cannabinoids studied were not predicted to be P-glycoprotein substrates, with the exception of 11-OH-THC, THCA, and HU-210), while almost all of them were P-glycoprotein inhibitors (with the exception of THCC and THCV). None of the cannabinoids studied proved to be BCRP, OAT1, OAT3, or OCT2 substrates, but all were predicted to be BCRP, BSEP, OAT3, OCT2, and OATP1B3 inhibitors (except THCA for the last one). Most cannabinoids studied were predicted to be OATP1B1 substrates and inhibitors (except THCC, THCV, CBV, including JWH-133, and including 11-OH-THC respectively). However, they were not found to be OCT1 substrates (except THCC, THCV, PH, THCA, and DMHP) or OCT1 inhibitors (except Delta8-THC, JWH-133, Nab, CBV, and CBN). These results suggest that there is potential for DDIs of the cannabinoids studied with conventional drugs when used concomitantly. [1] L. L. Anderson, M. G. Etchart, L. MacNair, M. H. Land, I. A. Mosesova, M. O. Bonn-Miller, J. C. Arnold. Cannabis and Cannabinoid Research, DOI: 10.1089/can.2020.0053. [2] S. K. Nigam, Nat. Rev. Discov. 2015, 14, 29. [3] ADMET Predictor® (2021) SimulationsPlus, Inc., USA, www.simulations-plus.com.

Cannabinoids ; ADMET ; Membrane transporters interactions ; In silico study

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