TY - JOUR
T1 - Inhibitory kinetics of fruit components on CYP2C19 activity
AU - Seki, Hiroyuki
AU - Akiyoshi, Takeshi
AU - Imaoka, Ayuko
AU - Ohtani, Hisakazu
N1 - Funding Information:
This work was supported in part by the Japan Research Foundation for JSPS Kakenhi Grant; Number 15K08596 [to H, O].
Publisher Copyright:
© 2019 The Japanese Society for the Study of Xenobiotics
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - 6′, 7′-dihydroxybergamottin
KW - Bergamottin
KW - Cytochrome P450 2C19
KW - Drug-food interaction
KW - Grapefruit juice
KW - Mechanism-based inhibition
KW - Resveratrol
KW - Time-dependent inhibition
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U2 - 10.1016/j.dmpk.2019.02.002
DO - 10.1016/j.dmpk.2019.02.002
M3 - Article
C2 - 30979536
AN - SCOPUS:85064012974
SN - 1347-4367
VL - 34
SP - 181
EP - 186
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 3
ER -