Abstract

(-)-∆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 {plus minus} 0.38 nmol/min/mg; K_m: 70 nM; CL_int: 15 {plus minus} 5.4 mL/min/mg and fm: 0.89 {plus minus} 0.31 at concentration << 70 nM) and CYP3A (CL_int: 2.0 {plus minus} 0.86 mL/min/mg; fm: 0.11 {plus minus} 0.050). 11-OH-THC (50 nM) was metabolized by CYP3A (CL_int: 0.26 {plus minus} 0.058 mL/min/mg; fm: 0.51 {plus minus} 0.11) and UGT2B7 (CL_int: 0.13 {plus minus} 0.027 mL/min/mg; fm: 0.25 {plus minus} 0.053). THC at 500 nM (CL_int: 4.7 {plus minus} 0.22 mL/min/mg) and 11-OH-THC at 50 nM (CL_int: 2.4 {plus minus} 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.

Significance Statement This is the first characterization and quantification of THC and 11-OH-THC depletion clearance by CYP and UGT enzymes in extrahepatic human tissues: intestine, fetal liver, lung, and placenta. These data can be used to predict, through PBPK M&S, systemic and tissue THC/11-OH-THC exposure, after inhalational and oral THC use, in both healthy and special populations (e.g. pregnant women).