Proceedings of The Physiological Society
University College Dublin (2009) Proc Physiol Soc 15, PC52
Interaction of Δ9-tetrahydrocannabinol and Buprenorphine with Multidrug Resistance Proteins in Human Placenta
D. Thajam1, C. P. Sibley1, D. E. Atkinson1
1. Maternal and Fetal Health Research Group, University of Manchester, Manchester, United Kingdom.
Drug misuse by pregnant women is a leading preventable cause of fetal and neonatal morbidity and mortality. It has been suggested that in both the UK and the USA 10-16% of pregnant women use illicit drugs. The level of exposure of any one fetus is likely to be determined by the capacity of the placenta to act as a barrier. The multi drug resistance proteins (MDRPs) P-glycoprotein (P-gp) and breast cancer resistance protein (BRCP) are located on the maternal facing (microvillous) plasma membrane of the placenta. In this location, these proteins may act to prevent xenobiotics in maternal plasma reaching the fetus at toxic concentrations. The aim of the present study was to determine whether two commonly used substances i.e. Δ9- tetrahydrocannabinol (THC) and buprenorphine (BUP) interact with P-gp and/or BCRP in human placental tissue. Term placentas were collected (with ethics committee approval and informed consent) within 30mins of delivery. Small villous fragments were dissected and used to measure accumulation of 3H-vinblastine (a P-gp substrate) and 3H-mitoxantrone (a BCRP substrate) in the presence or absence of 20µM THC or BUP. Accumulation at 10 mins (initial rate) and 120 mins (equilibrium) was measured in all cases. BUP had no significant effect on either vinblastine (n=5 placentas) or mitoxantrone (n=3) accumulation at 10 or 120 mins. THC caused a significant (p<0.05 Wilcoxon signed rank test, n=5) decrease in accumulation of vinblastine at 120 mins (50%) and there was a trend towards reduced accumulation (37%) at 10min (P=0.06 n=5). THC had no significant effect on mitoxantrone accumulation although there was a trend towards increased accumulation at both time points (10 mins 21% and 120mins 38% p=0.06 n=4). The reduced accumulation i.e. increased efflux of vinblastine in the presence of THC suggests stimulation of P-gp activity by this component of cannabis. These data are consistent with previous observations in insect cell membranes containing human P-gp where THC caused increased P-gp ATPase activity1. Extrapolating these in vitro data, we postulate that THC stimulation of placental P-gp activity would have a marked effect on the exposure of the fetus to other drugs which are substrates of this MDRP, taken by women using cannabis in pregnancy.
Where applicable, experiments conform with Society ethical requirements