Placental transfer of intravenous nicardipine and disposition into breast milk during the control of hypertension in women with pre-eclampsia.

OBJECTIVE: To assess nicardipine safety for fetuses and neonates. METHODS: Nicardipine was measured in maternal plasma (MP), umbilical cord arterial (UaP) and venous (UvP) plasma and breast milk (BrM) of 18 women with severe preeclampsia. RESULTS: Nicardipine was infused for a mean 11.9 ± 10.5 days before and 4.6 ± 1.6 days after delivery. Nicardipine dose and MP concentration were linearly correlated, as were MP with UaP, UvP, and BrM concentrations. The BrM/MP ratio was 0.06 to 0.30. The mean relative infant dose was 0.082%. CONCLUSION: Nicardipine is safe for fetuses and neonates due to its low levels of placental transfer and disposition in BrM.

Assessment of chimeric mice with humanized liver as a tool for predicting circulating human metabolites.

The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.