A physiological pharmacokinetic model for morphine disposition in the pregnant rat.

A physiological model was used to examine the disposition of morphine in the pregnant rat. In the model was incorporated an expression of both a linear and a nonlinear binding term of morphine to the maternal muscular tissue. Furthermore, the experimental data suggested that a diffusion-limited transport of morphine occurred across the placenta. Morphine showed a relatively high partition into the maternal kidney and muscle tissues. The concentration of morphine in the foetus was about 1.5 times higher than that of the maternal plasma, whereas the foetal brain concentration was about 4 times higher than that of the maternal plasma. The influence on morphine disposition by changes in both the tissue binding of the maternal muscle and the placental plasma flow was explored by model simulations. Due to the diffusion-limited transport of morphine across the placenta, a change in the placental plasma flow would only have an effect on the concentration-time profile of morphine in the foetal tissues if the plasma flow approached and became less than the diffusion clearance across the placenta. An increase in the partition of morphine into the maternal muscle produced an increase in the terminal half-life in all tissues including the foetus.