Identification of Enzymes Responsible for the N-Oxidation of Darexaban Glucuronide, the Pharmacologically Active Metabolite of Darexaban, and the Glucuronidation of Darexaban N-Oxides in Human Liver Microsomes

Shiraga, Toshifumi; Yajima, Kanako; Teragaki, Takuya; Suzuki, Katsuhiro; Hashimoto, Tadashi; Iwatsubo, Takafumi; Miyashita, Aiji; Usui, Takashi

doi:10.1248/bpb.35.413

Cited by 9 publications

(2 citation statements)

References 20 publications

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“…Notably, this statement remains true for states of potent CYP3A or P‐gp inhibition or induction. Based on several studies investigating the metabolic pathway of darexaban and darexaban glucuronide, the effect of CYP3A inhibition was expected to be small, since the main enzyme involved in the metabolism of darexaban is UGT1A which forms the active metabolite darexaban glucuronide as well as flavin‐containing mono‐oxygenase 3, which subsequently converts darexaban glucuronide into darexaban glucuronide‐ N ‐oxide . The involvement of CYP3A is limited to a very minor metabolic pathway where darexaban is converted into the metabolite YM‐228934 (data on file).…”

Section: Discussionmentioning

confidence: 99%

“…Based on several studies investigating the metabolic pathway of darexaban and darexaban glucuronide, the effect of CYP3A inhibition was expected to be small, since the main enzyme involved in the metabolism of darexaban is UGT1A which forms the active metabolite darexaban glucuronide as well as flavin-containing mono-oxygenase 3, which subsequently converts darexaban glucuronide into darexaban glucuronide-N-oxide. 10,17 The involvement of CYP3A is limited to a very minor metabolic pathway where darexaban is converted into the metabolite YM-228934 (data on file). YM-228934 was not analysed in the current study, since it had been shown in previous human clinical pharmacology studies that at the dose darexaban 60 mg, the concentrations of YM-228934 are below the limit of quantification (data on file).…”

Section: Discussionmentioning

confidence: 99%

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The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P‐glycoprotein

Groenendaal

Strabach²,

García-Hernández

et al. 2014

Clinical Pharm in Drug Dev

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We investigated the effects of ketoconazole on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite darexaban glucuronide (YM-222714) which almost entirely determines the antithrombotic effect. In this open-label, randomized, two-period crossover study, 26 healthy male volunteers received in one treatment period a single dose of darexaban 60 mg, and in the other treatment period, ketoconazole 400 mg once daily on Days 1-9 with a single dose of darexaban 60 mg on Day 4. Washout between periods was at least 1 week. The geometric mean ratio (90% confidence interval) of darexaban glucuronide (darexaban plus ketoconazole versus darexaban) for AUCinf was 1.11 (1.00, 1.23), and for Cmax 1.18 (1.03, 1.35). Darexaban concentrations remained very low (AUClast ∼196-fold lower) in relation to darexaban glucuronide concentrations. In conclusion, the PK of darexaban glucuronide was not affected to a clinically relevant degree by co-administration of the strong CYP3A/P-glycoprotein inhibitor, ketoconazole. The PK of the parent compound darexaban were changed, however, concentrations remained quantitatively insignificant in relation to the main active moiety, darexaban glucuronide.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P‐glycoprotein

Groenendaal

Strabach²,

García-Hernández

et al. 2014

Clinical Pharm in Drug Dev

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Flavin Monooxygenase Metabolism: Why Medicinal Chemists Should Matter

et al. 2014

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FMO enzymes (FMOs) play a key role in the processes of detoxification and/or bioactivation of specific pharmaceuticals and xenobiotics bearing nucleophilic centers. The N-oxide and S-oxide metabolites produced by FMOs are often active metabolites. The FMOs are more active than cytochromes in the brain and work in tandem with CYP3A4 in the liver. FMOs might reduce the risk of phospholipidosis of CAD-like drugs, although some FMOs metabolites seem to be neurotoxic and hepatotoxic. However, in silico methods for FMO metabolism prediction are not yet available. This paper reports, for the first time, a substrate-specificity and catalytic-activity model for FMO3, the most relevant isoform of the FMOs in humans. The application of this model to a series of compounds with unknown FMO metabolism is also reported. The model has also been very useful to design compounds with optimal clearance and in finding erroneous literature data, particularly cases in which substances have been reported to be FMO3 substrates when, in reality, the experimentally validated in silico model correctly predicts that they are not.

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Non-Cytochrome P450 Enzymes and Glucuronidation

Hutzler

Zientek

2015

New Horizons in Predictive Drug Metabolism and Pharmacokinetics

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While the metabolism of small molecule drugs has been dominated by the cytochrome P450 family of enzymes, many other enzyme families exist that help facilitate the conversion of lipophilic drug molecules to metabolites that may be readily excreted from the body. A shift in the chemical space that medicinal chemists are interrogating has led to generally more polar drug molecules, which has in turn has caused an increase in the prevalence of non-cytochrome P450 metabolic pathways. It is thus critical that drug metabolism scientists are aware of in vitro methods for identifying the role of these enzymes. For example, the role of the thermally labile metabolic enzyme flavin monooxygenase (FMO) is likely under-diagnosed due to the way in which in vitro incubations in human liver microsomes are conducted, with pre-incubations at 37 °C often devoid of NADPH. In addition, interest in the oxidative enzyme aldehyde oxidase (AO) has surged in recent years in response to its direct negative impact on clinical programs. Lastly, the UDP-glucuronosyltransferase (UGT) family of enzymes are highly problematic, with the extrapolation from in vitro systems to predict clearance to in vivo being a challenge. While many non-cytochrome P450 enzymes exist, the focus of this chapter will be on these three important enzyme systems.

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Identification of Enzymes Responsible for the N-Oxidation of Darexaban Glucuronide, the Pharmacologically Active Metabolite of Darexaban, and the Glucuronidation of Darexaban N-Oxides in Human Liver Microsomes

Cited by 9 publications

References 20 publications

The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P‐glycoprotein

The pharmacokinetics of darexaban (YM150), an oral direct factor Xa inhibitor, are not affected by ketoconazole, a strong inhibitor of CYP3A and P‐glycoprotein

Flavin Monooxygenase Metabolism: Why Medicinal Chemists Should Matter

Non-Cytochrome P450 Enzymes and Glucuronidation

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