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

(-)-∆ 9 -Tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis, a drug recreationally consumed by inhalation and orally. Physiologically based pharmacokinetic (PBPK) modeling can be used to predict systemic and tissue exposure to THC and its psychoactive metabolite, 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 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; K m : 70 nM; CL int : 15 ± 5.4 mL/min/mg and 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, 1st, 2nd trimester or term placentae microsomes. Using PBPK M&S, these data could be used in the future to predict systemic and tissue THC/11-OH-THC exposure in healthy and special populations.