Understanding the Mechanism and Extent of Transplacental Transfer of (−)‐∆⁹‐Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure

Abstract

Cannabis use during pregnancy may cause fetal toxicity driven by in utero exposure to (−)‐∆9‐tetrahydrocannabinol (THC) and its psychoactive metabolite, (±)‐11‐hydroxy‐∆9‐THC (11‐OH‐THC). THC concentrations in the human term fetal plasma appear to be lower than the corresponding maternal concentrations. Therefore, we investigated whether THC and its metabolites are effluxed by placental transporters using the dual cotyledon, dual perfusion, term human placenta. The perfusates contained THC alone (5 μM) or in combination (100–250 nM) with its metabolites (100 nM or 250 nM 11‐OH‐THC, 100 nM COOH‐THC), plus a marker of P‐glycoprotein (P‐gp) efflux (1 or 10 μM saquinavir), and a passive diffusion marker (106 μM antipyrine). All perfusions were conducted with (n = 7) or without (n = 16) a P‐gp/BCRP (breast‐cancer resistance protein) inhibitor, 4 μM valspodar. The maternal‐fetal and fetal‐maternal unbound cotyledon clearance indexes (m‐f‐CLu,c,i and f‐m‐CLu,c,i) were normalized for transplacental antipyrine clearance. At 5 μM THC, the m‐f‐CLu,c,i, 5.1 ± 2.1, was significantly lower than the f‐m‐CLu,c,i, 13 ± 6.1 (P = 0.004). This difference remained in the presence of valspodar or when the lower THC concentrations were perfused. In contrast, neither metabolite, 11‐OH‐THC/COOH‐THC, had significantly different m‐f‐CLu,c,i vs. f‐m‐CLu,c,i. Therefore, THC appears to be effluxed by placental transporter(s) not inhibitable by the P‐gp/BCRP antagonist, valspodar, while 11‐OH‐THC and COOH‐THC appear to passively diffuse across the placenta. These findings plus our previously quantified human fetal liver clearance, extrapolated to in vivo, yielded a THC fetal/maternal steady‐state plasma concentration ratio of 0.28 ± 0.09, comparable to that observed in vivo, 0.26 ± 0.10.

Placental disposition of cannabidiol: An ex vivo perfusion study

“…THC was suggested to be effluxed from the placenta by transporters other than P‐gp and BCRP. The two major THC metabolites, 11‐OH‐THC and COOH‐THC, passively diffused across the placenta 32 . The placental‐to‐maternal concentration ratio for THC (added to the maternal compartment) was 29–43, and those of 11‐OH‐THC and THC‐COOH were 32 and 5.4, respectively, in line with our findings.…”

“…The placental‐to‐maternal concentration ratio for THC (added to the maternal compartment) was 29–43, and those of 11‐OH‐THC and THC‐COOH were 32 and 5.4, respectively, in line with our findings. For each of the cannabinoids studied so far, the variation in placental accumulation was high; compared with the CBD coefficient of variation of 53% in the current study, the coefficient of variation was 52% for 5 μmol·L −1 THC, 58% for 100–250 nmol·L −1 THC, and 53% for 100–250 nmol·L −1 11‐OH‐THC 32 . This was likely due to the placental structure heterogeneity, which was previously demonstrated by us and discussed also for gene expression 15 .…”

“…In both cases, this resulted in cord‐to‐maternal blood concentrations of less than unity (.34–.44 and .68–.77, respectively) 22 . While the present article was in preparation, the fetal‐to‐maternal steady‐state plasma concentration ratio of THC was predicted to be .28 ± .09 based on the findings from an ex vivo perfusion study and the measured human fetal liver clearance 32 . THC was suggested to be effluxed from the placenta by transporters other than P‐gp and BCRP.…”

“…The perfusion medium contained albumin at concentrations relevant to human pregnancy, but it is unknown whether albumin is a major binding plasma protein for CBD 11 . Yet at least for THC, the transplacental transfer was not concentration‐dependent 32 . In addition, we did not assess the transplacental transfer of CBD's active metabolite, 7‐OH‐CBD 11 .…”

Clinical Pharmacology of Cannabinoid Therapeutics: Drug Interactions and Side Effects

“…Another question that arises is the safety of cannabis (therapeutic) use in pregnancy, see, for example, Kumar et al 7 Regarding the pharmacokinetics of THC, it is known that it is almost completely absorbed after oral administration and extensively metabolized in the liver. The systemic bioavailability of THC after oral administration is 6-7%, and 11-13% after oromucosal administration.…”