Inhibitory kinetics of fruit components on CYP2C19 activity.

Area of Science:

• Pharmacology
• Drug Metabolism
• Natural Product Chemistry

Background:

• Resveratrol (RSV), 6', 7'-dihydroxybergamottin (DHB), and bergamottin (BG) are fruit components with potential inhibitory effects on cytochrome P450 2C19 (CYP2C19).
• The precise mechanisms and potency of this inhibition have not been fully elucidated.
• Understanding these interactions is crucial for predicting drug-food interactions.

Purpose of the Study:

• To investigate the mode and kinetics of CYP2C19 inhibition by RSV and grapefruit juice components (DHB, BG).
• To determine the potential for drug-food interactions based on estimated intestinal concentrations.

Main Methods:

• Assessed the inhibition of CYP2C19-mediated omeprazole metabolism by RSV, DHB, and BG.
• Determined inhibition kinetics, including mechanism-based inhibition (MBI) and reversible inhibition.
• Calculated IC50 values and estimated in vivo inhibition based on likely intestinal concentrations.

Main Results:

• RSV and DHB demonstrated time-dependent inactivation of CYP2C19, indicative of MBI.
• BG exhibited both MBI and reversible inhibition, with MBI being the predominant mechanism.
• Estimated intestinal concentrations suggest >90% CYP2C19 inactivation following consumption of grapefruit or RSV-containing foods.

Conclusions:

• RSV, DHB, and BG are potent inhibitors of intestinal CYP2C19, primarily via MBI.
• Consumption of foods containing these components can lead to significant inhibition of CYP2C19 activity.
• These findings highlight the potential for clinically relevant drug-food interactions involving CYP2C19 substrates.