Maternal and Fetal Exposure to (-)-Δ⁹-tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice Is Differentially Impacted by P-glycoprotein and Breast Cancer Resistance Protein

Abstract

Δ 9 -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-tomaternal 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.

Efflux transporters in drug disposition during pregnancy

“…In particular, the maternal brain/maternal plasma AUC GMR for THC was only 28% lower in P-gp -/pregnant mice compared to WT pregnant mice. The unbound fraction of THC and its metabolites in maternal plasma and investigated tissues were not found to be significantly different among all genotypes (Chen et al, 2023). Also, none of the transporters known to be at the BBB of mice exhibited different expression levels in P-gp and/or Bcrp deficient mice compared to WT.…”

“…(Jiang et al, 2010;Tan et al, 2010;Tompkins et al, 2010;Pavek and Smutny, 2014). This review written by Dr. Mao's former graduate students and postdoctoral researchers summarizes first, the research conducted by Dr. Mao in his early career and subsequently, his work as a principal investigator carried out in his laboratory at the University of Washington (2002-2023.…”

CBD and THC in Special Populations: Pharmacokinetics and Drug–Drug Interactions

“…Animal studies suggested that THC is the substrate of P-gp and BCRP [ 90 , 91 ]. In contrast, Chen et al concluded from a Madin–Darby Canine Kidney cell study and an animal study that THC and most of its metabolites are not substrates of P-gp and BCRP, except for 11-COOH-THC, which is a poor substrate of BCRP [ 92 , 93 ].…”

Placental disposition of cannabidiol: An ex vivo perfusion study

“…For instance, the cord‐to‐maternal blood concentration ratios measured 5–26 h after THC smoking were .17–.7 and .13–.61 for THC and 9‐carboxy‐THC, respectively 8 . Efflux transport by P‐glycoprotein (P‐gp) and the breast cancer resistance protein (BCRP) was suggested to be a minor contributor to the pharmacokinetics of THC and THC‐COOH, 9 and THC was not considerably metabolized by term placental microsomes 10 . Although THC and CBD differ in their interactions with drug‐metabolizing enzymes and potentially with drug transporters, they share the property of sequestration in fatty tissues due to their high lipophilicity 11 .…”