Maternal and Fetal Exposure to (-)-D9-tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice Is Differentially Impacted by P-glycoprotein and Breast Cancer Resistance ProteinS

(-)-D9-tetrahydrocannabinol (THC) is the primary pharmacological active constituent of cannabis. 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are respectively the active and nonactive circulating metabolites of THC in humans. While previ-ous animal studies reported that THC could be a substrate of mouse P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), we have shown, in vitro, that only THC-COOH is a weak sub-strate of human BCRP, but not of P-gp. To confirm these findings and to investigate the role of P-gp and/or Bcrp in the maternal-fetal disposition of THC and its metabolites, we administrated 3 mg/kg of THC retro-orbitally to FVB wild-type (WT), P-gp-/-, Bcrp-/-, or P-gp-/-/Bcrp-/-pregnant mice on gestation day 18 and estimated the area under the concentration-time curve (AUC) of the cannabi-noids in the maternal plasma, maternal brain, placenta, and fetus, as well as the tissue/maternal plasma AUC geometric mean ratios (GMRs) using a pooled data bootstrap approach. We found that the dose-normalized maternal plasma AUCs of THC in P-gp-/-and P-gp-/-/Bcrp-/-mice, and the placenta-to-maternal plasma AUC GMR of THC in Bcrp-/- mice were 279%, 271%, and 167% of those in WT mice, respectively. Surprisingly, the tissue-to-maternal plasma AUC GMRs of THC and its major metabolites in the mater- nal brain, placenta, or fetus in P-gp-/-, Bcrp-/- or P-gp-/-/Bcrp-/- mice were 28-78% of those in WT mice. This study revealed that P-gp and Bcrp do not play a role in limiting maternal brain and fetal exposure to THC and its major metabolites in pregnant mice.