Quantifying Hepatic Enzyme Kinetics of (-)-∆⁹-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, 11-OH-THC,...

The prevalence of cannabis use and the concentrations of the psychoactive cannabinoid in cannabis, (-)-∆⁹-tetrahydrocannabinol (THC), are rising. Physiologically based pharmacokinetic modeling and simulations (PBPK M&S) can mechanistically predict exposure of THC and its major and active metabolite, 11-hydroxy-THC (11-OH-THC). To build a THC/11-OH-THC PBPK model, mechanistic information about the disposition of these compounds is necessary, including the drug-metabolizing enzymes (DMEs) involved and the fraction metabolized (fm) and metabolic kinetic parameters (intrinsic clearance, maximal formation rate, and K_m) via the identified enzymes. We previously identified and quantified the fm of DMEs involved in hepatic depletion of THC and 11-OH-THC. In this study, we extend this work to characterize the enzyme kinetics of THC and 11-OH-THC by monitoring their depletion and formation of some of their metabolites in pooled human liver microsomes. A P450 and UDP-glucuronosyltransferase (UGT) kinetic model was fitted to the concentration-time depletion/formation profiles to establish the contribution and kinetics of the individual DME pathways. CYP2C9 pathway was the major pathway for depletion of THC (fm = 0.91, K_m,u = 3 nM) and formation of 11-OH-THC. The remaining THC depletion pathway was attributed to CYP2D6. 11-OH-THC was depleted by UGTs (fm = 0.67 and K_m,u = 39 nM), CYP3A4 (fm = 0.18, K_m,u = 824 nM), and CYP2C9 (fm = 0.15, K_m,u = 33 nM). These mechanistic in vitro data can be used to predict the exposure of THC and 11-OH-THC in healthy and special populations, including in the presence of drug-drug interactions, via PBPK M&S.