Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison
Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The O -demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to parent in animals. The...
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Published in | Drug metabolism and disposition Vol. 37; no. 4; pp. 802 - 808 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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United States
American Society for Pharmacology and Experimental Therapeutics
01.04.2009
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Abstract | Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and
venous thrombotic diseases. The O -demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to
parent in animals. The aim of this study was to identify the sulfotransferases (SULTs) responsible for the sulfation reaction.
Apixaban undergoes O -demethylation catalyzed by cytochrome P450 enzymes to O -demethyl apixaban, and then is conjugated by SULTs to form O -demethyl apixaban sulfate. Of the five human cDNA-expressed SULTs tested, SULT1A1 and SULT1A2 exhibited significant levels
of catalytic activity for formation of O -demethyl apixaban sulfate, and SULT1A3, SULT1E1, and SULT2A1 showed much lower catalytic activities. In human liver S9, quercetin,
a highly selective inhibitor of SULT1A1 and SULT1E1, inhibited O -demethyl apixaban sulfate formation by 99%; 2,6-dichloro-4-nitrophenol, another inhibitor of SULT1A1, also inhibited this
reaction by >90%; estrone, a competitive inhibitor for SULT1E1, had no effect on this reaction. The comparable K m values for formation of O -demethyl apixaban sulfate were 41.4 μM (human liver S9), 36.8 μM (SULT1A1), and 70.8 μM (SULT1A2). Because of the high level
of expression of SULT1A1 in liver and its higher level of catalytic activity for formation of O -demethyl apixaban sulfate, SULT1A1 might play a major role in humans for formation of O -demethyl apixaban sulfate. O -Demethyl apixaban was also investigated in liver S9 of mice, rats, rabbits, dogs, monkeys, and humans. The results indicated
that liver S9 samples from dogs, monkeys, and humans had higher activities for formation of O -demethyl apixaban sulfate than those of mice, rats, and rabbits. |
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AbstractList | Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The O-demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to parent in animals. The aim of this study was to identify the sulfotransferases (SULTs) responsible for the sulfation reaction. Apixaban undergoes O-demethylation catalyzed by cytochrome P450 enzymes to O-demethyl apixaban, and then is conjugated by SULTs to form O-demethyl apixaban sulfate. Of the five human cDNA-expressed SULTs tested, SULT1A1 and SULT1A2 exhibited significant levels of catalytic activity for formation of O-demethyl apixaban sulfate, and SULT1A3, SULT1E1, and SULT2A1 showed much lower catalytic activities. In human liver S9, quercetin, a highly selective inhibitor of SULT1A1 and SULT1E1, inhibited O-demethyl apixaban sulfate formation by 99%; 2,6-dichloro-4-nitrophenol, another inhibitor of SULT1A1, also inhibited this reaction by >90%; estrone, a competitive inhibitor for SULT1E1, had no effect on this reaction. The comparable K(m) values for formation of O-demethyl apixaban sulfate were 41.4 microM (human liver S9), 36.8 microM (SULT1A1), and 70.8 microM (SULT1A2). Because of the high level of expression of SULT1A1 in liver and its higher level of catalytic activity for formation of O-demethyl apixaban sulfate, SULT1A1 might play a major role in humans for formation of O-demethyl apixaban sulfate. O-Demethyl apixaban was also investigated in liver S9 of mice, rats, rabbits, dogs, monkeys, and humans. The results indicated that liver S9 samples from dogs, monkeys, and humans had higher activities for formation of O-demethyl apixaban sulfate than those of mice, rats, and rabbits. Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The O -demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to parent in animals. The aim of this study was to identify the sulfotransferases (SULTs) responsible for the sulfation reaction. Apixaban undergoes O -demethylation catalyzed by cytochrome P450 enzymes to O -demethyl apixaban, and then is conjugated by SULTs to form O -demethyl apixaban sulfate. Of the five human cDNA-expressed SULTs tested, SULT1A1 and SULT1A2 exhibited significant levels of catalytic activity for formation of O -demethyl apixaban sulfate, and SULT1A3, SULT1E1, and SULT2A1 showed much lower catalytic activities. In human liver S9, quercetin, a highly selective inhibitor of SULT1A1 and SULT1E1, inhibited O -demethyl apixaban sulfate formation by 99%; 2,6-dichloro-4-nitrophenol, another inhibitor of SULT1A1, also inhibited this reaction by >90%; estrone, a competitive inhibitor for SULT1E1, had no effect on this reaction. The comparable K m values for formation of O -demethyl apixaban sulfate were 41.4 μM (human liver S9), 36.8 μM (SULT1A1), and 70.8 μM (SULT1A2). Because of the high level of expression of SULT1A1 in liver and its higher level of catalytic activity for formation of O -demethyl apixaban sulfate, SULT1A1 might play a major role in humans for formation of O -demethyl apixaban sulfate. O -Demethyl apixaban was also investigated in liver S9 of mice, rats, rabbits, dogs, monkeys, and humans. The results indicated that liver S9 samples from dogs, monkeys, and humans had higher activities for formation of O -demethyl apixaban sulfate than those of mice, rats, and rabbits. Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The O-demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to parent in animals. The aim of this study was to identify the sulfotransferases (SULTs) responsible for the sulfation reaction. Apixaban undergoes O-demethylation catalyzed by cytochrome P450 enzymes to O-demethyl apixaban, and then is conjugated by SULTs to form O-demethyl apixaban sulfate. Of the five human cDNA-expressed SULTs tested, SULT1A1 and SULT1A2 exhibited significant levels of catalytic activity for formation of O-demethyl apixaban sulfate, and SULT1A3, SULT1E1, and SULT2A1 showed much lower catalytic activities. In human liver S9, quercetin, a highly selective inhibitor of SULT1A1 and SULT1E1, inhibited O-demethyl apixaban sulfate formation by 99%; 2,6-dichloro-4-nitrophenol, another inhibitor of SULT1A1, also inhibited this reaction by >90%; estrone, a competitive inhibitor for SULT1E1, had no effect on this reaction. The comparable K(m) values for formation of O-demethyl apixaban sulfate were 41.4 microM (human liver S9), 36.8 microM (SULT1A1), and 70.8 microM (SULT1A2). Because of the high level of expression of SULT1A1 in liver and its higher level of catalytic activity for formation of O-demethyl apixaban sulfate, SULT1A1 might play a major role in humans for formation of O-demethyl apixaban sulfate. O-Demethyl apixaban was also investigated in liver S9 of mice, rats, rabbits, dogs, monkeys, and humans. The results indicated that liver S9 samples from dogs, monkeys, and humans had higher activities for formation of O-demethyl apixaban sulfate than those of mice, rats, and rabbits. |
Author | Kan He Donglu Zhang Joseph M. Luettgen Lifei Wang Nirmala Raghavan W. Griffith Humphreys Robert M. Knabb Donald J. Pinto |
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Snippet | Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and
venous thrombotic diseases. The O... Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The... |
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SubjectTerms | Animals Biocatalysis Biotransformation Chromatography, High Pressure Liquid Enzyme Inhibitors - pharmacology Humans Mass Spectrometry Methylation Pyrazoles - metabolism Pyrazoles - pharmacokinetics Pyridones - metabolism Pyridones - pharmacokinetics Species Specificity Sulfates - metabolism Sulfotransferases - antagonists & inhibitors Sulfotransferases - metabolism |
Title | Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison |
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