RT Journal Article SR Electronic T1 Maternal and Fetal Exposure to (-)-Δ9-tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice Is Differentially Impacted by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP DMD-AR-2022-001110 DO 10.1124/dmd.122.001110 A1 Xin Chen A1 Jashvant D. Unadkat A1 Qingcheng Mao YR 2022 UL http://dmd.aspetjournals.org/content/early/2022/11/29/dmd.122.001110.abstract AB (-)-Δ9-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 previous 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 substrate 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 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 cannabinoids 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 maternal 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. Significance Statement This study systematically investigated whether P-gp and/or Bcrp in pregnant mice can alter the disposition of THC, 11-OH-THC, and THC-COOH. Surprisingly, except for Bcrp, which limits placental (but not fetal) exposure to THC, we found that P-gp-/-, Bcrp-/-, and/or P-gp-/-/Bcrp-/- significantly decreased exposure to THC and/or its metabolites in maternal brain, placenta, or fetus. The mechanistic basis for this decrease is unclear and needs further investigation. If replicated in humans, P-gp or BCRP based drug-cannabinoid interactions are not of concern.