6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]

Publication Date:
2018-11-06
Publisher:
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Print ISSN:
0090-9556
Electronic ISSN:
1521-009X
Topics:
Chemistry and Pharmacology
Medicine
Published by:
http://www.aspet.org/
_version_ 1836399079500808192
autor Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
beschreibung 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H -indole-3-carboxylic acid (PF-06409577) is a direct activator of the human β 1-containing adenosine monophosphate-activated protein kinase (AMPK) isoforms. The clearance mechanism of PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)–mediated glucuronidation to an acyl glucuronide metabolite of PF-06409577 [(2 S ,3 S ,4 S ,5 R ,6 S )-6-((6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1 H -indole-3-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2 H -pyran-2-carboxylic acid (M1)], which retains selective activation of human β 1-containing AMPK isoforms. This paper describes a detailed characterization of the human UGT isoform(s) responsible for glucuronidation of PF-06409577 to M1. Studies using a panel of 13 human recombinant UGT (hrUGT) enzymes indicated that PF-06409577 was converted to M1 in a highly selective fashion by UGT1A1, which was further verified in human liver microsomes treated with specific chemical inhibitors, and in different UGT1A1 expressers. Conversion of PF-06409577 to M1 by UGT1A1 occurred in a relatively selective fashion, compared with β -estradiol (ES), a conventional probe substrate of UGT1A1. The Michaelis-Menten constant ( K M ) and V max values describing the formation of M1 from PF-06409577 in hrUGT1A1 and microsomal preparations from human intestine, liver, and kidney ranged from 131 to 212 μ M ( K M ) and 107–3834 pmol/min per milligram ( V max ) in the presence of 2% bovine serum albumin. Relative activity factors (RAF) were determined for UGT1A1 using PF-06409577 and ES to enable estimation of intrinsic clearance from various tissues. RAF values from PF-06409577 and ES were generally comparable with the exception of intestinal microsomes, where ES overestimated the RAF of UGT1A1 due to glucuronidation by intestinal UGT1A8 and UGT1A10. Our results suggest the potential utility of PF-06409477 as a selective probe UGT1A1 substrate for UGT reaction phenotyping and inhibition studies in preclinical discovery/development.
citation_standardnr 6352790
datenlieferant ipn_articles
feed_id 1915
feed_publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
feed_publisher_url http://www.aspet.org/
insertion_date 2018-11-06
journaleissn 1521-009X
journalissn 0090-9556
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
quelle Drug Metabolism and Disposition
relation http://dmd.aspetjournals.org/cgi/content/short/46/12/1836?rss=1
search_space articles
shingle_author_1 Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
shingle_author_2 Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
shingle_author_3 Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
shingle_author_4 Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
shingle_catch_all_1 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H -indole-3-carboxylic acid (PF-06409577) is a direct activator of the human β 1-containing adenosine monophosphate-activated protein kinase (AMPK) isoforms. The clearance mechanism of PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)–mediated glucuronidation to an acyl glucuronide metabolite of PF-06409577 [(2 S ,3 S ,4 S ,5 R ,6 S )-6-((6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1 H -indole-3-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2 H -pyran-2-carboxylic acid (M1)], which retains selective activation of human β 1-containing AMPK isoforms. This paper describes a detailed characterization of the human UGT isoform(s) responsible for glucuronidation of PF-06409577 to M1. Studies using a panel of 13 human recombinant UGT (hrUGT) enzymes indicated that PF-06409577 was converted to M1 in a highly selective fashion by UGT1A1, which was further verified in human liver microsomes treated with specific chemical inhibitors, and in different UGT1A1 expressers. Conversion of PF-06409577 to M1 by UGT1A1 occurred in a relatively selective fashion, compared with β -estradiol (ES), a conventional probe substrate of UGT1A1. The Michaelis-Menten constant ( K M ) and V max values describing the formation of M1 from PF-06409577 in hrUGT1A1 and microsomal preparations from human intestine, liver, and kidney ranged from 131 to 212 μ M ( K M ) and 107–3834 pmol/min per milligram ( V max ) in the presence of 2% bovine serum albumin. Relative activity factors (RAF) were determined for UGT1A1 using PF-06409577 and ES to enable estimation of intrinsic clearance from various tissues. RAF values from PF-06409577 and ES were generally comparable with the exception of intestinal microsomes, where ES overestimated the RAF of UGT1A1 due to glucuronidation by intestinal UGT1A8 and UGT1A10. Our results suggest the potential utility of PF-06409477 as a selective probe UGT1A1 substrate for UGT reaction phenotyping and inhibition studies in preclinical discovery/development.
Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_2 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H -indole-3-carboxylic acid (PF-06409577) is a direct activator of the human β 1-containing adenosine monophosphate-activated protein kinase (AMPK) isoforms. The clearance mechanism of PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)–mediated glucuronidation to an acyl glucuronide metabolite of PF-06409577 [(2 S ,3 S ,4 S ,5 R ,6 S )-6-((6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1 H -indole-3-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2 H -pyran-2-carboxylic acid (M1)], which retains selective activation of human β 1-containing AMPK isoforms. This paper describes a detailed characterization of the human UGT isoform(s) responsible for glucuronidation of PF-06409577 to M1. Studies using a panel of 13 human recombinant UGT (hrUGT) enzymes indicated that PF-06409577 was converted to M1 in a highly selective fashion by UGT1A1, which was further verified in human liver microsomes treated with specific chemical inhibitors, and in different UGT1A1 expressers. Conversion of PF-06409577 to M1 by UGT1A1 occurred in a relatively selective fashion, compared with β -estradiol (ES), a conventional probe substrate of UGT1A1. The Michaelis-Menten constant ( K M ) and V max values describing the formation of M1 from PF-06409577 in hrUGT1A1 and microsomal preparations from human intestine, liver, and kidney ranged from 131 to 212 μ M ( K M ) and 107–3834 pmol/min per milligram ( V max ) in the presence of 2% bovine serum albumin. Relative activity factors (RAF) were determined for UGT1A1 using PF-06409577 and ES to enable estimation of intrinsic clearance from various tissues. RAF values from PF-06409577 and ES were generally comparable with the exception of intestinal microsomes, where ES overestimated the RAF of UGT1A1 due to glucuronidation by intestinal UGT1A8 and UGT1A10. Our results suggest the potential utility of PF-06409477 as a selective probe UGT1A1 substrate for UGT reaction phenotyping and inhibition studies in preclinical discovery/development.
Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_3 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H -indole-3-carboxylic acid (PF-06409577) is a direct activator of the human β 1-containing adenosine monophosphate-activated protein kinase (AMPK) isoforms. The clearance mechanism of PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)–mediated glucuronidation to an acyl glucuronide metabolite of PF-06409577 [(2 S ,3 S ,4 S ,5 R ,6 S )-6-((6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1 H -indole-3-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2 H -pyran-2-carboxylic acid (M1)], which retains selective activation of human β 1-containing AMPK isoforms. This paper describes a detailed characterization of the human UGT isoform(s) responsible for glucuronidation of PF-06409577 to M1. Studies using a panel of 13 human recombinant UGT (hrUGT) enzymes indicated that PF-06409577 was converted to M1 in a highly selective fashion by UGT1A1, which was further verified in human liver microsomes treated with specific chemical inhibitors, and in different UGT1A1 expressers. Conversion of PF-06409577 to M1 by UGT1A1 occurred in a relatively selective fashion, compared with β -estradiol (ES), a conventional probe substrate of UGT1A1. The Michaelis-Menten constant ( K M ) and V max values describing the formation of M1 from PF-06409577 in hrUGT1A1 and microsomal preparations from human intestine, liver, and kidney ranged from 131 to 212 μ M ( K M ) and 107–3834 pmol/min per milligram ( V max ) in the presence of 2% bovine serum albumin. Relative activity factors (RAF) were determined for UGT1A1 using PF-06409577 and ES to enable estimation of intrinsic clearance from various tissues. RAF values from PF-06409577 and ES were generally comparable with the exception of intestinal microsomes, where ES overestimated the RAF of UGT1A1 due to glucuronidation by intestinal UGT1A8 and UGT1A10. Our results suggest the potential utility of PF-06409477 as a selective probe UGT1A1 substrate for UGT reaction phenotyping and inhibition studies in preclinical discovery/development.
Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_4 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1 H -indole-3-carboxylic acid (PF-06409577) is a direct activator of the human β 1-containing adenosine monophosphate-activated protein kinase (AMPK) isoforms. The clearance mechanism of PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)–mediated glucuronidation to an acyl glucuronide metabolite of PF-06409577 [(2 S ,3 S ,4 S ,5 R ,6 S )-6-((6-chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1 H -indole-3-carbonyl)oxy)-3,4,5-trihydroxytetrahydro-2 H -pyran-2-carboxylic acid (M1)], which retains selective activation of human β 1-containing AMPK isoforms. This paper describes a detailed characterization of the human UGT isoform(s) responsible for glucuronidation of PF-06409577 to M1. Studies using a panel of 13 human recombinant UGT (hrUGT) enzymes indicated that PF-06409577 was converted to M1 in a highly selective fashion by UGT1A1, which was further verified in human liver microsomes treated with specific chemical inhibitors, and in different UGT1A1 expressers. Conversion of PF-06409577 to M1 by UGT1A1 occurred in a relatively selective fashion, compared with β -estradiol (ES), a conventional probe substrate of UGT1A1. The Michaelis-Menten constant ( K M ) and V max values describing the formation of M1 from PF-06409577 in hrUGT1A1 and microsomal preparations from human intestine, liver, and kidney ranged from 131 to 212 μ M ( K M ) and 107–3834 pmol/min per milligram ( V max ) in the presence of 2% bovine serum albumin. Relative activity factors (RAF) were determined for UGT1A1 using PF-06409577 and ES to enable estimation of intrinsic clearance from various tissues. RAF values from PF-06409577 and ES were generally comparable with the exception of intestinal microsomes, where ES overestimated the RAF of UGT1A1 due to glucuronidation by intestinal UGT1A8 and UGT1A10. Our results suggest the potential utility of PF-06409477 as a selective probe UGT1A1 substrate for UGT reaction phenotyping and inhibition studies in preclinical discovery/development.
Lapham, K., Lin, J., Novak, J., Orozco, C., Niosi, M., Di, L., Goosen, T. C., Ryu, S., Riccardi, K., Eng, H., Cameron, K. O., Kalgutkar, A. S.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_title_1 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
shingle_title_2 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
shingle_title_3 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
shingle_title_4 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
timestamp 2025-06-30T23:37:16.594Z
titel 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
titel_suche 6-Chloro-5-[4-(1-Hydroxycyclobutyl)Phenyl]-1H-Indole-3-Carboxylic Acid is a Highly Selective Substrate for Glucuronidation by UGT1A1, Relative to {beta}-Estradiol [Articles]
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