Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study.
OBJECTIVE
Drugs of abuse affect pregnancy outcomes, however, the mechanisms in which cannabis exerts its effects are not well understood. The aim of this study was to examine the influence of short-term (1-2 hours) exposure to cannabidiol, a major phytocannabinoid, on human placental breast cancer resistance protein function.


METHODS
The in vitro effect of short-term exposure to cannabidoil on breast cancer resistance protein in BeWo and Jar cells (MCF7/P-gp cells were used for comparison) was tested with mitoxantrone uptake, and nicardipine was used as positive control. The ex vivo perfused cotyledon system was used for testing the effect of cannabidoil on glyburide transport across the placenta. Glyburide (200 ng/mL) was introduced to maternal and fetal compartments through a recirculating 2 hour perfusion, and its transplacental transport was tested with (n = 8) or without (n = 8) cannabidoil.


RESULTS
(1) Cannabidoil inhibition of breast cancer resistance protein-dependent mitoxantrone efflux was concentration dependent and of a noncell type specific nature (P < .0001); (2) In the cotyledon perfusion assay, the administration of cannabidoil to the maternal perfusion media increased the female/male ratio of glyburide concentrations (1.3 ± 0.1 vs 0.8 ± 0.1 at 120 minutes of perfusion, P < .001).


CONCLUSIONS
(1) Placental breast cancer resistance protein function is inhibited following even a short-term exposure to cannabidoil; (2) the ex vivo perfusion assay emphasize this effect by increased placental penetration of glyburide to the fetal compartment; and (3) these findings suggest that marijuana consumption enhances placental barrier permeability to xenobiotics and could endanger the developing fetus. Thus, the safety of drugs that are breast cancer resistance protein substrates is questionable during cannabis consumption by pregnant women.
Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Valeria
V
Feinshtein
Offer
O
Erez
Zvi
Z
Ben-Zvi
Tamar
T
Eshkoli
Boaz
B
Sheizaf
Eyal
E
Sheiner
Gershon
G
Holcberg
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000704:Analysis of Variance; D002185:Cannabidiol / Q000493:pharmacokinetics* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005905:Glyburide / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D008942:Mitoxantrone / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009529:Nicardipine / Q000378:metabolism; D010477:Perfusion / Q000379:methods; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D002185:Cannabidiol; D008942:Mitoxantrone; D009529:Nicardipine; D005905:Glyburide
BeWo; Jar cells; breast cancer resistance protein (BCRP); cannabidiol; human placental perfusion; marijuana