Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor

Iwatsuki, Yoshiyuki; Sato, Takayuki; Moritani, Yumiko; Shigenaga, Takeshi; Suzuki, Mami; Kawasaki, Tomihisa; Funatsu, Toshiyuki; Kaku, Seiji

doi:10.1016/j.ejphar.2011.10.009

Cited by 41 publications

(32 citation statements)

References 20 publications

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“…Darexaban maleate (YM150 monomaleate; Fig. 1) is an oral, specific, direct inhibitor of factor Xa that has shown antithrombotic potency in preclinical model studies, with minimal effects on bleeding compared with vitamin K antagonists Saitoh et al, 2007;Iwatsuki et al, 2011). Darexaban is being developed for the prevention of venous thromboembolism in patients undergoing hip or knee replacement surgery, prevention of stroke in patients with atrial fibrillation, and prevention of ischemic events after recent acute coronary syndrome (Eriksson et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver and Intestine

Shiraga¹,

Yajima²,

Suzuki³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Darexaban maleate is a novel oral direct factor Xa inhibitor, which is under development for the prevention of venous thromboembolism. Darexaban glucuronide was the major component in plasma after oral administration of darexaban to humans and is the pharmacologically active metabolite. In this study, we identified UDPglucuronosyltransferases (UGTs) responsible for darexaban glucuronidation in human liver microsomes (HLM) and human intestinal microsomes (HIM). In HLM, the K m value for darexaban glucuronidation was >250 M. In HIM, the reaction followed substrate inhibition kinetics, with a K m value of 27.3 M. Among recombinant human UGTs, UGT1A9 showed the highest intrinsic clearance for darexaban glucuronidation, followed by UGT1A8, -1A10, and -1A7. All other UGT isoforms were inactive toward darexaban. The K m value of recombinant UGT1A10 for darexaban glucuronidation (34.2 M) was comparable to that of HIM. Inhibition studies using typical UGT substrates suggested that darexaban glucuronidation in both HLM and HIM was mainly catalyzed by UGT1A8, -1A9, and -1A10. Fatty acid-free bovine serum albumin (2%) decreased the unbound K m for darexaban glucuronidation from 216 to 17.6 M in HLM and from 35.5 to 18.3 M in recombinant UGT1A9. Recent studies indicated that the mRNA expression level of UGT1A9 is extremely high among UGT1A7, -1A8, -1A9, and -1A10 in human liver, whereas that of UGT1A10 is highest in the intestine. Thus, the present results strongly suggest that darexaban glucuronidation is mainly catalyzed by UGT1A9 and UGT1A10 in human liver and intestine, respectively. In addition, UGT1A7, -1A8, and -1A9 play a minor role in human intestine.

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Section: Introductionmentioning

confidence: 99%

Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver and Intestine

Shiraga¹,

Yajima²,

Suzuki³

et al. 2011

Drug Metab Dispos

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“…The latter value is at least 10-fold higher compared with the oral direct FXa inhibitors that are currently in use or in clinical development (rivaroxaban, apixaban, edoxaban, betrixaban) [2]. The in vivo antithrombotic activity of darexaban after oral administration is produced by its active metabolite, YM-222714 [16][17][18]. Results of pharmacokinetic analysis demonstrated that darexaban is rapidly absorbed and extensively metabolized into YM-222714.…”

Section: Darexaban: Pre-clinical Data and Clinical Development 41 Phmentioning

confidence: 99%

“…Warfarin also exerted antithrombotic effects dose dependently; however, in clinically relevant doses, warfarin significantly prolonged bleeding time. The anticoagulation activity of darexaban was not affected by the presence of food [16][17][18].…”

Section: Darexaban: Pre-clinical Data and Clinical Development 41 Phmentioning

confidence: 99%

Novel oral anticoagulants: focus on the direct factor Xa inhibitor darexaban

Apostolakis

Lip

2012

Expert Opinion on Investigational Drugs

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Darexaban is a potent direct factor Xa inhibitor that demonstrated impressive pharmacokinetic properties in pre-clinical studies. It was further successfully evaluated in the ONYX program for the prevention of venous thromboembolism in patients undergoing hip replacement. Finally, in the Phase II RUBY-1 trial, darexaban was tested on the top of standard antiplatelet therapy for the prevention of ischemic events in acute coronary syndrome (ACS) patients. Despite the fact that darexaban had a relatively uneventful clinical evaluation program, its further development was recently discontinued. This decision could probably reflect the non-favorite results in commercially attractive indications, such as secondary prevention post-ACS and the increased competition for less common or short-term indications such stroke prevention in AF or VTE prophylaxis respectively.

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“…[1][2][3] Clinical studies have shown that the major metabolite of darexaban in human plasma is its phenolic O-glucuronide (darexaban glucuronide, YM-222714, Fig. 1) and that plasma exposure of parent darexaban is very low and does not exceed 1% of that of darexaban glucuronide, indicating that darexaban is extensively eliminated by firstpass metabolism via glucuronidation.…”

Section: Identification Of Enzymes Responsible For the N-oxidation Ofmentioning

confidence: 99%

“…Interestingly, the inhibitory activity of YM-222714 against factor Xa is similar to that of darexaban in vitro. 2,3) YM-222714 is therefore the active metabolite and primary determinant of the pharmacological effect of darexaban after oral administration in humans. In contrast, the pharmacological activity of YM-222714 N-oxides was extremely weak compared with that of darexaban or its glucuronide, YM-222714 (unpublished data).…”

Section: Identification Of Enzymes Responsible For the N-oxidation Ofmentioning

confidence: 99%

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

Yajima

Teragaki

et al. 2012

Biological & Pharmaceutical Bulletin

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Darexaban maleate is a novel oral direct factor Xa inhibitor. Darexaban glucuronide (YM-222714) was the major component in plasma after oral administration of darexaban to humans and is the pharmacologically active metabolite. Additionally, YM-222714 N-oxides were detected as minor metabolites in human plasma and urine. It is possible that YM-222714 N-oxides are formed by the N-oxidation of YM-222714 and/or the glucuronidation of darexaban N-oxides (YM-542845) in vivo. The former reaction is the pharmacological inactivation process. In this study, we identified the human enzymes responsible for YM-222714 N-oxidation and the uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) isoforms involved in YM-542845 glucuronidation in vitro. YM-222714 N-oxidation activity was detected in human liver microsomes (HLM), but not in human intestinal microsomes. In HLM, YM-222714 N-oxidation activities were significantly correlated with flavin-containing monooxygenase (FMO) marker enzyme activities (p<0.001) and inhibited by methimazole, a typical inhibitor of FMOs. Recombinant human FMO3 and FMO1 were capable of efficiently catalyzing YM-222714 N-oxidation, but not FMO5 or any recombinant human cytochrome P450 (CYP) isoforms. Considering the mRNA expression levels of FMO isoforms in human liver, these results strongly suggest that YM-222714 N-oxidation in HLM is mainly catalyzed by FMO3. In HLM, YM-542845 glucuronidation was strongly inhibited by typical substrates for UGT1A8, UGT1A9, and UGT1A10. Recombinant human UGT1A7, UGT1A8, UGT1A9, and UGT1A10 were capable of catalyzing YM-542845 glucuronidation, and UGT1A9 exhibited the highest intrinsic clearance. Considered together with the expression levels of UGT isoforms in human liver, these results strongly suggest that YM-542845 glucuronidation in HLM is mainly catalyzed by UGT1A9.

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Biochemical and pharmacological profile of darexaban, an oral direct factor Xa inhibitor

Cited by 41 publications

References 20 publications

Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver and Intestine

Identification of UDP-Glucuronosyltransferases Responsible for the Glucuronidation of Darexaban, an Oral Factor Xa Inhibitor, in Human Liver and Intestine

Novel oral anticoagulants: focus on the direct factor Xa inhibitor darexaban

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

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