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• W2040872040 abstract "Usnic acid is a component of nutritional supplements promoted for weight loss that have been associated with liver-related adverse events including mild hepatic toxicity, chemical hepatitis, and liver failure requiring transplant. To determine if metabolism factors might have had a role in defining individual susceptibility to hepatotoxicity, in vitro metabolism studies were undertaken using human plasma, hepatocytes, and liver subcellular fractions. Usnic acid was metabolized to form three monohydroxylated metabolites and two regio-isomeric glucuronide conjugates of the parent drug. Oxidative metabolism was mainly by cytochrome P450 (CYP) 1A2 and glucuronidation was carried out by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A3. In human hepatocytes, usnic acid at 20 microM was not an inducer of CYP1A2, CYP2B6, or CYP3A4 relative to positive controls omeprazole, phenobarbital, and rifampicin, respectively. Usnic acid was a relatively weak inhibitor of CYP2D6 and a potent inhibitor of CYP2C19 (the concentration eliciting 50% inhibition (IC(50)) = 9 nM) and CYP2C9 (IC(50) = 94 nM), with less potent inhibition of CYP2C8 (IC(50) = 1.9 microM) and CYP2C18 (IC(50) = 6.3 microM). Pre-incubation of microsomes with usnic acid did not afford any evidence of time-dependent inhibition of CYP2C19, although evidence of slight time-dependent inhibition of CYP2C9 (K(I) = 2.79 microM and K(inact) = 0.022 min(-1)) was obtained. In vitro data were used with SimCYP(R)to model potential drug interactions. Based on usnic acid doses in case reports of 450 mg to >1 g day(-1), these in vitro data indicate that usnic acid has significant potential to interact with other medications. Individual characteristics such as CYP1A induction status, co-administration of CYP1A2 inhibitors, UGT1A1 polymorphisms, and related hyperbilirubinaemias, or co-administration of low therapeutic index CYP2C substrates could work alone or in consort with other idiosyncrasy risk factors to increase the risk of adverse events and/or hepatotoxicity. Thus, usnic acid in nutritional supplements might be involved as both victim and/or perpetrator in clinically significant drug-drug interactions." @default.
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• W2040872040 date "2008-03-01" @default.
• W2040872040 modified "2023-10-01" @default.
• W2040872040 title "Metabolism and related human risk factors for hepatic damage by usnic acid containing nutritional supplements" @default.
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• W2040872040 doi "https://doi.org/10.1080/00498250701802514" @default.
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