Characterizing and Quantifying Extrahepatic Metabolism of (-)-Δ⁹-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, (±)-11-Hydroxy-Δ⁹-THC (11-OH-THC)

(-)-Δ⁹-Tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis, a drug recreationally consumed orally or by inhalation. Physiologically based pharmacokinetic (PBPK) modeling can be used to predict systemic and tissue exposure to THC and its psychoactive metabolite, (±)-11-hydroxy-Δ⁹-THC (11-OH-THC). To populate a THC/11-OH-THC PBPK model, we previously characterized the depletion clearance of THC (by CYP2C9) and 11-OH-THC (by UDP-glucuronosyltransferase (UGT), CYP3A, and CYP2C9) in adult human liver microsomes. Here we focused on quantifying extrahepatic depletion clearance of THC/11-OH-THC, important after oral (intestine) and inhalational (lung) consumption of THC as well as prenatal THC use (placenta and fetal liver). THC (500 nM) was metabolized in adult human intestinal microsomes (n = 3-5) by CYP2C9 [V_max: 1.1 ± 0.38 nmol/min/mg; Michaelis-Menten constant (K_m): 70 nM; intrinsic clearance (CL_int): 15 ± 5.4 ml/min/mg; fraction metabolized (fm): 0.89 ± 0.31 at concentration ≪ 70 nM] and CYP3A (CL_int: 2.0 ± 0.86 ml/min/mg; fm: 0.11 ± 0.050). 11-OH-THC (50 nM) was metabolized by CYP3A (CL_int: 0.26 ± 0.058 ml/min/mg; fm: 0.51 ± 0.11) and UGT2B7 (CL_int: 0.13 ± 0.027 ml/min/mg; fm: 0.25 ± 0.053). THC at 500 nM (CL_int: 4.7 ± 0.22 ml/min/mg) and 11-OH-THC at 50 nM (CL_int: 2.4 ± 0.13 ml/min/mg) were predominately (fm: 0.99 and 0.80, respectively) metabolized by CYP3A in human fetal liver microsomes (n = 3). However, we did not observe significant depletion of THC/11-OH-THC in adult lung, first trimester, second trimester, or term placentae microsomes. Using PBPK modeling and simulation, these data could be used in the future to predict systemic and tissue THC/11-OH-THC exposure in healthy and special populations. SIGNIFICANCE STATEMENT: This is the first characterization and quantification of (-)-Δ⁹-tetrahydrocannabinol (THC) and (±)-11-hydroxy-Δ⁹-THC (11-OH-THC) depletion clearance by cytochrome P450 and UDP-glucuronosyltransferase enzymes in extrahepatic human tissues: intestine, fetal liver, lung, and placenta. These data can be used to predict, through physiologically based pharmacokinetic modeling and simulation, systemic and tissue THC/11-OH-THC exposure after inhalational and oral THC use in both healthy and special populations (e.g., pregnant women).