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Research ArticleArticle

Acyl Glucuronidation and Glucosidation of a New and Selective Endothelin ETA Receptor Antagonist in Human Liver Microsomes

Cuyue Tang, Jerome H. Hochman, Bennett Ma, Raju Subramanian and Kamlesh P. Vyas
Drug Metabolism and Disposition January 2003, 31 (1) 37-45; DOI: https://doi.org/10.1124/dmd.31.1.37
Cuyue Tang
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Jerome H. Hochman
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Bennett Ma
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Raju Subramanian
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Kamlesh P. Vyas
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Abstract

Compound A [(+)-(5S,6R,7R)-2-isopropylamino-7-[4-methoxy-2-((2R)-3-methoxy-2-methylpropyl)-5-(3,4-methylenedioxyphenyl) cyclopenteno [1,2-b] pyridine 6-carboxylic acid] is a new and selective endothelin ETA receptor antagonist. It underwent significant acyl glucuronidation and acyl glucosidation in human liver microsomes supplemented with UDP-glucuronic acid (UDPGA) and UDP-glucose (UDPG). These two conjugations were observed in a panel of human liver microsomal samples (n = 16) that gave rise to varying activities but with no significant correlation with each other in the native and activator-treated microsomal preparations (r2 ≤ 0.4, p > 0.05). The lack of correlation may be explained by the involvement of multiple UDP-glucuronosyltransferases (UGTs; UGT1A1, 1A3, 1A9, 2B7 and 2B15) in the glucuronidation but essentially solely UGT2B7 in the glucosidation. Both reactions conformed to monophasic Michaelis-Menten kinetics in human liver microsomes. The glucuronidation reaction exhibited apparent Km values (mean ± S.E.) for compound A and UDPGA of 8.4 ± 0.6 and 605 ± 35 μM, respectively, whereas the values for the glucosidation reaction were 10.2 ± 1.5 and 670 ± 120 μM, respectively. In both pooled human liver microsomes and expressed UGT2B7, UDPG and UDPGA competitively inhibited their counterpart conjugations withKi values close to theirKm values, indicating a comparable affinity of the enzyme toward these two nucleotide sugars. We herein report a drug acyl glucoside formed in human liver microsomes at a considerable turnover rate and provide the evidence for a UGT isoform (UGT2B7) capable of transferring both glucuronic acid and glucose from UDPGA and UDPG to an aglycone.

Footnotes

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferases
    UDPGA
    UDP-glucuronic acid
    UDPG
    UDP-glucose
    compound A
    (+)-(5S,6R,7R)-2-isopropylamino-7-[4-methoxy-2-((2R)-3-methoxy-2-methylpropyl)-5-(3,4-methylenedioxyphenyl) cyclopenteno [1,2-b] pyridine 6-carboxylic acid
    compound B
    (5S,6R,7R)-5-(1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-(methyloxy)phenyl]-2-[(1-methylethyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid
    HPLC
    high performance liquid chromatography
    LC-MS
    liquid chromatography mass spectrometry
    ESI
    electrospray ionization
    • Received July 5, 2002.
    • Accepted September 26, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (1)
Drug Metabolism and Disposition
Vol. 31, Issue 1
1 Jan 2003
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Research ArticleArticle

Acyl Glucuronidation and Glucosidation of a New and Selective Endothelin ETA Receptor Antagonist in Human Liver Microsomes

Cuyue Tang, Jerome H. Hochman, Bennett Ma, Raju Subramanian and Kamlesh P. Vyas
Drug Metabolism and Disposition January 1, 2003, 31 (1) 37-45; DOI: https://doi.org/10.1124/dmd.31.1.37

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Research ArticleArticle

Acyl Glucuronidation and Glucosidation of a New and Selective Endothelin ETA Receptor Antagonist in Human Liver Microsomes

Cuyue Tang, Jerome H. Hochman, Bennett Ma, Raju Subramanian and Kamlesh P. Vyas
Drug Metabolism and Disposition January 1, 2003, 31 (1) 37-45; DOI: https://doi.org/10.1124/dmd.31.1.37
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