Effects of 6-paradol, an unsaturated ketone from gingers, on cytochrome P450-mediated drug metabolism

• Published in: Bioorganic & medicinal chemistry letters 2017-04, Vol.27 (8), p.1826-1830
• Main Authors: Kim, Hyeong Jun, Kim, In Sook, Rehman, Shaheed Ur, Ha, Sang Keun, Nakamura, Katsunori, Yoo, Hye Hyun
• Format: Article
• Language: English
• Subjects: 6-Paradol; CYP inhibition; Cytochrome P-450 Enzyme Inhibitors - chemistry; Cytochrome P-450 Enzyme Inhibitors - pharmacology; Cytochrome P-450 Enzyme System - metabolism; Drug-drug interaction; Ginger; Guaiacol - analogs & derivatives; Guaiacol - chemistry; Guaiacol - pharmacology; Humans; Ketones - chemistry; Ketones - pharmacology; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Pharmaceutical Preparations - metabolism; Recombinant Proteins - metabolism; Unsaturated ketone; Zingiber officinale - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.02.047

[Display omitted] Paradols are unsaturated ketones produced by biotransformation of shogaols in gingers. Among them, 6-paradol has been investigated as a new drug candidate due to its anti-inflammatory, apoptotic, and neuroprotective activities. In this study, the inhibitory effects of 6-paradol on the activities of cytochrome P450 (CYP) enzymes were investigated with human liver microsomes and recombinant CYP isozymes. 6-Paradol showed concentration-dependent inhibitory effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 isozymes, with IC50 values ranging from 3.8 to 21.4µM in recombinant CYP isozymes. However, the inhibition was not potentiated following pre-incubation, indicating that 6-paradol is not a mechanism-based inhibitor. These results suggest that pharmacokinetic drug-drug interactions might occur with 6-paradol, which must be considered in the process of new drug development.