Qingchen Zhang
University of Florida
Co-Authors: Philip W Melchert, Barry Setlow, Christopher R McCurdy, John S Markowitz
University of Florida
Background: In the state of Florida, smoked cannabis flower is the primary form of medical cannabis (MC) dispensed for various qualifying conditions. MC is recommended for conditions including cancer, epilepsy, glaucoma, HIV/AIDS, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and others. Given its common usage, concerns exist regarding potential drug-drug interactions (DDIs) when conventional medications including pulmonary therapeutics are used concurrently with MC.
Objective: This study aimed to collect and characterize cannabis smoke condensate (CSC) from combusted cannabis and assess the influence of the in vitro inhibitory effects on the drug-metabolizing enzymes (DMEs) carboxylesterase 1 (CES1) and six cytochrome P450 enzymes (CYP) 2C8, 2C9, 2C19, 2D6, 2B6, and 2E1 expressed in human lung S9 (HluS9).
Methods: Standardized cannabis cigarettes sourced from the NIH National Institute of Drug Abuse Supply Program (NIDA) were combusted in an enclosed smoke exposure system. The generated smoke was routed through an ultra-cold condenser, allowing for the collection of CSC. The CSC was analyzed for the presence of eight major CBs and metabolites via LC-MS/MS. In vitro enzyme inhibition studies were conducted using human lung S9 to evaluate the potential inhibitory effect of CSC on CES1, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2B6, and CYP2E1.
Results: A total of 5.0 ± 1.5 mg per cigarette of CSC was collected, which contained 0.02 ± 0.01% cannabidiol (CBD), 0.94 ± 0.44% cannabinol (CBN), 6.46 ± 3.76% ∆9-tetrahydrocannabinol (THC), and 0.14 ± 0.07% cannabigerol (CBG) of the total condensate. In vitro enzyme kinetics studies revealed that to CES1 in HluS9, the inhibition mechanism of CSC was reversible mixed-type complete inhibition, with an inhibition constant (Ki) of 0.12 ± 0.08 μM using THC as the index compound. CYP1A2 and CYP3A showed activities in Hlus9. The half-maximal inhibitory concentration (IC50) of CSC for CYP3A inhibition was determined to be 17.85 μM with THC as the index compound.
Conclusions: CSC exhibited strong inhibition of CES1 and mild inhibitory effects on CYP3A activity. Further investigations are warranted to elucidate the inhibition mechanisms and assess the inhibitory effects on other active CYPs in HluS9.