Synthetic and Metabolic Studies of Deuterium Labelled Drugs

摘要

Incorporation of deuterium atoms to API's (active pharmaceutical ingredients) can result in improved stability and pharmacokinetic profile over the parent structures, while retaining their efficacy. Increased strength in carbon-deuterium bonds may allow deuterated compounds to be metabolized at slower rates and used in lower dosages than all hydrogen analogs. In our studies we have synthesized market available compounds, such as fluoxetine, with deuterium in the place of hydrogen at the primary metabolic sites of the molecule, either the N-methyl or O-methyl groups of the CNS compounds we work with. After characterization and purification of our new compounds, bio-assays are run using CYP, an enzyme found in human liver cells. The 3A4 (metabolism of O-methyl) and 2D6 (metabolism of N-methyl) form of the enzyme are used in our in vitro studies. To evaluate the pharmacokinetic profile of our synthesized compounds, bio-assays are run side by side with the parent, hydrogen analogs. Our studies are evaluated by monitoring the disappearance of methyl groups over time using NMR and HPLC.