Inhibitory effects of sesamin on CYP2C9-dependent 7-hydroxylation of S-warfarin

• Published in: Drug metabolism and pharmacokinetics Vol. 35; no. 4; pp. 368 - 373
• Main Authors: Fujii, Miharu, Yasuda, Kaori, Sakaki, Toshiyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2020
• Subjects: Competitive inhibition; CYP2C9; Cytochrome P-450 CYP2C9 - metabolism; Dioxoles - chemistry; Dioxoles - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Human liver microsomes; Humans; Hydroxylation - drug effects; Kinetics; Lignans - chemistry; Lignans - pharmacology; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Molecular Structure; Sesamin; Warfarin; Warfarin - chemistry; Warfarin - metabolism; SC1; CYP2C9; Sesamin; Warfarin; P450 or CYP; UGT; SC2; Human liver microsomes; Competitive inhibition; SULT; HPLC
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2020.05.002

A recent report demonstrated that sesamin strongly and non-competitively inhibits S-warfarin 7-hydroxylation activity in human liver microsomes with a Ki value of 0.2 μM. This finding suggests that sesamin predominantly binds to CYP2C9 at another site for which it has a higher affinity than its affinity for the active site, thereby inhibiting the activity of CYP2C9 non-competitively. In this study, we found that sesamin competitively inhibited the 7-hydroxylation activity of S-warfarin in human liver microsomes with a Ki value of 15.7 μM. In addition, the recombinant CYP2C9-dependent 7-hydroxylation activity of S-warfarin was competitively inhibited by sesamin with a Ki value of 13.1 μM. These results are consistent with the fact that sesamin is a good substrate of CYP2C9, and its activity follows Michaelis-Menten kinetics. As the plasma concentration of sesamin after its administration is usually lower than 0.01 μM, the inhibition of S-warfarin metabolism by sesamin does not appear to be severe. CYP2C9-dependent competitive reactions and inhibitions between S-warfarin and sesamin. [Display omitted]