“…When using the oral clearance values it is assumed that the compound is completely absorbed, and that the liver is the major organ of clearance. For this study, 10 compounds were selected from the literature where the metabolism has been shown to involve FMO: benzydamine (Taniguchi-Takizawa (Adali et al, 1999), olanzapine (Korprasertthaworn et al, 2015), ranitidine (Chung et al, 2000), cimetidine (Cashman et al, 1993), moclobemide (Hoskins et al, 2001), itopride (Mushiroda et al, 2000), clozapine (Tugnait et al, 1997), tamoxifen (Parte and Kupfer, 2005), and tozasertib (Ballard et al, 2007) (Fig. 1).…”
Flavin-containing monooxygenases (FMO) are metabolic enzymes mediating the oxygenation of nucleophilic atoms such as nitrogen, sulfur, phosphorus, and selenium. These enzymes share similar properties to the cytochrome P450 system but can be differentiated through heat inactivation and selective substrate inhibition by methimazole. This study investigated 10 compounds with varying degrees of FMO involvement to determine the nature of the correlation between human in vitro and in vivo unbound intrinsic clearance. To confirm and quantify the extent of FMO involvement six of the compounds were investigated in human liver microsomal (HLM) in vitro assays using heat inactivation and methimazole substrate inhibition. Under these conditions FMO contribution varied from 21% (imipramine) to 96% (itopride). Human hepatocyte and HLM intrinsic clearance (CL) data were scaled using standard methods to determine the predicted unbound intrinsic clearance (predicted CL) for each compound. This was compared with observed unbound intrinsic clearance (observed CL) values back calculated from human pharmacokinetic studies. A good correlation was observed between the predicted and observed CL using hepatocytes ( = 0.69), with 8 of the 10 compounds investigated within or close to a factor of 2. For HLM the in vitro-in vivo correlation was maintained ( = 0.84) but the accuracy was reduced with only 3 out of 10 compounds falling within, or close to, twofold. This study demonstrates that human hepatocytes and HLM can be used with standard scaling approaches to predict the human in vivo clearance for FMO substrates.
“…When using the oral clearance values it is assumed that the compound is completely absorbed, and that the liver is the major organ of clearance. For this study, 10 compounds were selected from the literature where the metabolism has been shown to involve FMO: benzydamine (Taniguchi-Takizawa (Adali et al, 1999), olanzapine (Korprasertthaworn et al, 2015), ranitidine (Chung et al, 2000), cimetidine (Cashman et al, 1993), moclobemide (Hoskins et al, 2001), itopride (Mushiroda et al, 2000), clozapine (Tugnait et al, 1997), tamoxifen (Parte and Kupfer, 2005), and tozasertib (Ballard et al, 2007) (Fig. 1).…”
Flavin-containing monooxygenases (FMO) are metabolic enzymes mediating the oxygenation of nucleophilic atoms such as nitrogen, sulfur, phosphorus, and selenium. These enzymes share similar properties to the cytochrome P450 system but can be differentiated through heat inactivation and selective substrate inhibition by methimazole. This study investigated 10 compounds with varying degrees of FMO involvement to determine the nature of the correlation between human in vitro and in vivo unbound intrinsic clearance. To confirm and quantify the extent of FMO involvement six of the compounds were investigated in human liver microsomal (HLM) in vitro assays using heat inactivation and methimazole substrate inhibition. Under these conditions FMO contribution varied from 21% (imipramine) to 96% (itopride). Human hepatocyte and HLM intrinsic clearance (CL) data were scaled using standard methods to determine the predicted unbound intrinsic clearance (predicted CL) for each compound. This was compared with observed unbound intrinsic clearance (observed CL) values back calculated from human pharmacokinetic studies. A good correlation was observed between the predicted and observed CL using hepatocytes ( = 0.69), with 8 of the 10 compounds investigated within or close to a factor of 2. For HLM the in vitro-in vivo correlation was maintained ( = 0.84) but the accuracy was reduced with only 3 out of 10 compounds falling within, or close to, twofold. This study demonstrates that human hepatocytes and HLM can be used with standard scaling approaches to predict the human in vivo clearance for FMO substrates.
“…In general, FMO enzymes have not been reported to be very inducible. However, induction of FMO4 and FMO5 cDNA has been reported in human hepatocytes by the drug rifampicin (Rae et al 2001 ), and the tricyclic antidepressants imipramine and chlorpromazine were reported to upregulate recombinant FMO3 catalyzed methimazole S -oxidation in a concentration-dependent manner (Adali et al 1998 , 1999 ; Cherrington et al 1998 ) (Table 3 ). In addition, FMO5 mRNA was upregulated in HepG2 cells by the natural product (herbal medicine) St. John’s wort and its active component hyperforin, as well as by the synthetic progestin R5020 in a breast cancer cell line that stably expresses B-receptors (YB cells) (Miller et al 1997 ).…”
Section: Resultsmentioning
confidence: 99%
“…Chlorazepine N -oxide was also reduced back to chlorpromazine (Beckett et al 1988 ; Cashman et al 1993b ; Chetty et al 1994 ; Jaworski et al 1990 ; Ohmiya and Mehendale 1984 ). This example illustrates the complexity of drug metabolism and activity when metabolic reactions are components of multiple metabolic pathways and effects (Adali et al 1998 , 1999 ). Fig.…”
This is an overview of the metabolic reactions of drugs, natural products, physiological compounds, and other (general) chemicals catalyzed by flavin monooxygenase (FMO), monoamine oxidase (MAO), NAD(P)H quinone oxidoreductase (NQO), and molybdenum hydroxylase enzymes (aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR)), including roles as substrates, inducers, and inhibitors of the enzymes. The metabolism and bioactivation of selected examples of each group (i.e., drugs, “general chemicals,” natural products, and physiological compounds) are discussed. We identified a higher fraction of bioactivation reactions for FMO enzymes compared to other enzymes, predominately involving drugs and general chemicals. With MAO enzymes, physiological compounds predominate as substrates, and some products lead to unwanted side effects or illness. AOX and XOR enzymes are molybdenum hydroxylases that catalyze the oxidation of various heteroaromatic rings and aldehydes and the reduction of a number of different functional groups. While neither of these two enzymes contributes substantially to the metabolism of currently marketed drugs, AOX has become a frequently encountered route of metabolism among drug discovery programs in the past 10–15 years. XOR has even less of a role in the metabolism of clinical drugs and preclinical drug candidates than AOX, likely due to narrower substrate specificity.
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