Placental Transfer and Fetal Elimination of Morphine-3-β-glucuronide in the Pregnant Baboon

Abstract

The glucuronide metabolites of several widely used drugs are detected in fetal plasma after maternal drug administration. However, the disposition of these metabolites is poorly understood and clinical concerns have been raised about accumulation of active metabolites in the fetus. For this reason, morphine-3-beta-glucuronide (M3G), an active metabolite of morphine, was studied to provide quantitative data on disposition. Maternal, fetal, and bidirectional placental clearances of M3G were measured in three pregnant baboons. During maternal infusion of M3G to steady-state, the glucuronide metabolite readily appeared in fetal plasma achieving a mean +/- S.D. fetal-to-maternal concentration ratio of 0.79 +/- 0.04. In paired maternal and fetal infusions, steady-state clearances were 53 +/- 3 (maternal), 1.5 +/- 0.5 (maternal-to-fetal), 2.6 +/- 0.1 (fetal-to-maternal), and -0.70 +/- 0.6 ml x min(-1) (fetal). These clearance values support bidirectional transfer of M3G across the placenta and indicate negligible direct clearance from the fetus. The clearance of M3G across the placenta is more than 20-fold less than that of morphine. Despite this low index of permeability, placental transfer contributes significantly to the glucuronide pool in the fetus. Placental transfer emerges as the major clearance pathway for the glucuronide from the fetus and suggests a component of active efflux. What is more, the results do not support the concept of sequestration in the fetal intestine as a significant route of clearance. Together these results clarify the distribution and clearance of glucuronides in the pregnant primate and facilitate prediction of fetal exposure to active metabolites.