Disposition of morphine in tissues of the pregnant rat and foetus following single and continuous intraperitoneal administration to the mother

Foetal exposure to maternally administered opiates such as morphine represe nt a serious human health problem but disposition studies in man are diffic ult to perform. Morphine disposition was therefore investigated in pregnant rats and their foetuses near term as a model. Disposition was examined eit her following intraperitoneal dosing as a single dose or continuous infusio n. A high-pressure liquid chromatography assay for morphine in plasma and t issue was developed and validated. Following the single morphine dose, foetal distribution was rapid and conce ntrations in foetal and placental tissue were from 2 . 6 (whole foetus) to 27 . 6 (placenta) times higher compared with maternal plasma. The rank orde r of the area under the concentration vs time curve (AUC) of morphine in ti ssues was: placenta greater than or equal to foetal liver > foetal brain > whole foetus > maternal brain. The foetal brain to maternal brain AUC ratio for morphine was 9 . 5, suggesting large differences in their blood-brain barrier permeability. Following continuous administration of morphine there were significant linear relationships between maternal plasma and tissue c oncentrations with the same rank order as the single dose study. However, f ollowing continuous administration the relative amount of morphine in place nta and foetal liver was reduced by half and one-third, respectively, compa red with the single dose study. These results document why the rat foetus is particularly susceptible to th e pharmacodynamic effects of morphine following maternal administration.