Effects of water-soluble organic co-solvents on the metabolic kinetics of drugs in rat liver microsomes

Abstract

The aim of this research was to explore how different water-miscible organic co-solvents, such as methanol, acetonitrile, dimethyl sulphoxide, and dioxane, influence the kinetic characteristics of enzymes in rat liver microsomes that metabolize drugs. Our study revealed that the impact of these co-solvents on enzyme activity was highly dependent on the specific metabolic route involved and the concentration of the co-solvent used. Methanol and dimethyl sulphoxide showed a notable increase in the Km of p-nitrophenol hydroxylation, while acetonitrile showed activation of this metabolic pathway. Interestingly, dioxane resulted in a significant increase in the Km of metoprolol metabolism, while acetonitrile decreased the Km of metabolite 3 formation. In addition, our study findings revealed that the Vmax/Km ratio was significantly affected by dimethyl sulphoxide and dioxane, suggesting their unsuitability for characterizing Cytochrome450 mediated reactions. On the other hand, methanol and acetonitrile were found to be suitable solvents for solubilizing substances that Cytochrome 450s metabolise, as long as their concentration remained below 0.5% v/v. Overall, our study sheds light on the potential effects of chemical co-solvents that are water soluble on enzyme kinetics and highlights the importance of carefully selecting appropriate solvents to study the in vitro metabolism of drugs.