Understanding the Mechanism and Extent of Transplacental Transfer of (-)-∆ 9 -Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure.
Level 5 - mechanism / opinion, no new human data
Ex vivo human placental perfusion model and mechanistic pharmacokinetic extrapolation
PubMed 37278090 · doi:10.1002/cpt.2964
What was done
Researchers evaluated the transplacental clearance of THC and its metabolites using an ex vivo dual-cotyledon, dual-perfused human term placenta model. Perfusates contained THC alone (5 μM) or combined (100–250 nM) with metabolites (100 or 250 nM 11-OH-THC, 100 nM COOH-THC), alongside saquinavir (P-gp marker) and antipyrine (passive diffusion marker). Perfusions were run with (n = 7) or without (n = 16) 4 μM valspodar (a P-gp/BCRP inhibitor). Maternal-to-fetal and fetal-to-maternal unbound cotyledon clearance indexes (m-f-CL u,c,i and f-m-CL u,c,i) were calculated and used with fetal liver clearance data to model in vivo fetal/maternal steady-state concentration ratios.
What was found
At 5 μM THC, the maternal-to-fetal clearance index (5.1 ± 2.1) was significantly lower than the fetal-to-maternal clearance index (13 ± 6.1, P = 0.004). This difference persisted at lower THC concentrations and with valspodar present. Neither 11-OH-THC nor COOH-THC demonstrated directional clearance differences. Pharmacokinetic modeling predicted an in vivo fetal/maternal steady-state plasma concentration ratio of 0.28 ± 0.09, matching the reported in vivo ratio of 0.26 ± 0.10.
Why it matters
The findings demonstrate that lower fetal THC concentrations at term are driven by active fetal-to-maternal placental efflux mediated by a transporter distinct from P-gp and BCRP, while its metabolites cross primarily via passive diffusion.
Limits
The study is limited to term placentas (total n = 23) and does not characterize transport dynamics across earlier trimesters. The specific transporter protein mediating THC efflux was not identified beyond excluding P-gp and BCRP.
Cited by
- supports Tetrahydrocannabinol (THC) crosses the human placenta directly.