Inhibitory kinetics of fruit components on CYP2C19 activity |
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| Affiliation: | 1. Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan;2. Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan;3. Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan;4. Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang-Ming University, Taipei, Taiwan;5. National Research Institute of Chinese Medicine, Taipei, Taiwan;6. Department and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan;7. Institute of Biopharmaceutical Sciences, School of Pharmacy, National Yang-Ming University, Taipei, Taiwan;8. Division of General Internal Medicine and Geriatrics, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan;9. Chang Gung University College of Medicine, Taoyuan City, Taiwan;10. Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic;11. Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan |
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| Abstract: | It has been suggested that the fruit components resveratrol (RSV), 6′, 7′-dihydroxybergamottin (DHB), and bergamottin (BG) might inhibit cytochrome P450 2C19 (CYP2C19) activity, but the mode and potency of such inhibition are yet to be investigated. This study aimed to investigate the mode and kinetics of the inhibition of CYP2C19-based omeprazole metabolism by RSV or grapefruit juice components (DHB or BG). RSV and DHB reduced CYP2C19 activity in a preincubation time-dependent manner, suggesting that they inactivated CYP2C19 via mechanism-based inhibition (MBI). Although BG inactivated CYP2C19 in a preincubation time- and concentration-dependent manner, suggesting that both MBI and reversible inhibition contributed to these effects, the concentration required to achieve 50% inhibition was 26-fold higher for reversible inhibition than for MBI (0.859 and 0.0331 μM, respectively), indicating that the inhibition of CYP2C19 by BG is primarily attributable to MBI. Based on the estimated intestinal concentrations of these components, it is considered that >90% of CYP2C19 would be inactivated after the consumption of normal amounts of grapefruit juice or RSV-containing substances. In conclusion, these findings suggest that food containing these components has the potential to evoke drug-food interactions caused by the MBI of intestinal CYP2C19 activity in the clinical setting. |
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| Keywords: | Cytochrome P450 2C19 Grapefruit juice 6′, 7′-dihydroxybergamottin Bergamottin Resveratrol Mechanism-based inhibition Time-dependent inhibition Drug-food interaction CYP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" Cytochome P450 TDI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" time-dependent inhibition MBI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" mechanism-based inhibition GFJ" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" grapefruit juice RSV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" resveratrol DHB" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" 6′, 7′-dihydroxybergamottin BG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" bergamottin 50% of inhibitory concentration AUC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" area under the plasma concentration-time curve peak plasma concentration the inactivation rate constant the maximal inactivation rate constant the concentration of the inhibitor required to achieve half-maximal inactivation OPZ" },{" #name" :" keyword" ," $" :{" id" :" kwrd0185" }," $$" :[{" #name" :" text" ," _" :" omeprazole |
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