841.1 - P-gp and Bcrp Exert Differential Impacts on Maternal and Fetal Exposure to Tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice
Tuesday, April 5, 2022
9:17 AM – 9:28 AM
Room: 111 AB - Pennsylvania Convention Center
Introduction: Recent studies have revealed that cannabis is the second most used drug after alcohol in the US. Evidence shows that cannabis use in adolescents and young adults is associated with adverse neurocognitive reactions. Studies also show that cannabis use by pregnant women has been consistently increasing over time. Cannabis use among these special populations is expected to further increase with recent trends toward legalization of recreational consumption, representing a potential but great public health concern. This symposium is therefore timely with respect to understanding neurotoxicity of cannabinoids in infants and adolescents.
Xin Chen (University of Washington), Jashvant Unadkat (University of Washington), Qingcheng Mao (University of Washington)
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 lt; 0.05 were considered statistically significant. In Bcrp-/- pregnant mice, the placenta/maternal plasma AUC ratio for THC was 188% (p lt; 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 lt; 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.
