P‐gp and Bcrp Exert Differential Impacts on Maternal and Fetal Exposure to Tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice

In the United States, cannabis consumption is increasing. (-)-Δ9 -tetrahydrocannabinol (THC) is the primary pharmacological active constituent of cannabis, while 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are active and nonactive circulating metabolites of THC in humans, respectively. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are ATP-binding cassette efflux transporters important for drug disposition, including brain penetration and fetal exposure. Our previous in vitro transport study showed that only THC-COOH is a weak substrate of human BCRP, while previous animal studies reported that THC and its metabolites could be substrates of the P-gp and BCRP orthologs in mice and macaques. To further investigate the roles of P-gp and 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-/- , and Bcrp-/- pregnant mice on gestational day 18, and determined maternal, placental, and fetal concentrations of THC and its metabolites by LC-MS/MS. The AUCs of THC and its major metabolites were estimated using a pooled data bootstrap approach. Differences in tissue/maternal plasma AUC ratios between WT and P-gp-/- or Bcrp-/- were compared via unpaired parametric t-test, and differences with p values of < 0.05 were considered statistically significant. In Bcrp-/- pregnant mice, the placenta/maternal plasma AUC ratio for THC was 188% (p < 0.05) of respective AUC ratio in WT pregnant mice. In P-gp-/- pregnant mice, the maternal brain/maternal plasma AUC ratio for THC, maternal brain/maternal plasma and fetus/maternal plasma AUC ratios for 11-OH-THC, and fetus/maternal plasma AUC ratio for THC-COOH were 29%, 65%, 49%, and 54% (p < 0.05) of respective AUC ratio in WT pregnant mice. There were no significant differences in fetal exposure of THC in either P-gp-/- or Bcrp-/- mice, and in fetal exposure of 11-OH-THC and THC-COOH in Bcrp-/- mice, compared to WT mice. In conclusion, this study revealed that P-gp and Bcrp exerted differential impacts on maternal brain, placental, and fetal exposure to cannabinoids in pregnant mice. P-gp and Bcrp do not seem to play a role in limiting fetal exposure to THC and its major metabolites; but could differentially alter maternal brain exposure to the cannabinoids.