@article {Tang37, author = {Cuyue Tang and Jerome H. Hochman and Bennett Ma and Raju Subramanian and Kamlesh P. Vyas}, title = {Acyl Glucuronidation and Glucosidation of a New and Selective Endothelin ETA Receptor Antagonist in Human Liver Microsomes}, volume = {31}, number = {1}, pages = {37--45}, year = {2003}, doi = {10.1124/dmd.31.1.37}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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 {\textpm} S.E.) for compound A and UDPGA of 8.4 {\textpm} 0.6 and 605 {\textpm} 35 μM, respectively, whereas the values for the glucosidation reaction were 10.2 {\textpm} 1.5 and 670 {\textpm} 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/31/1/37}, eprint = {https://dmd.aspetjournals.org/content/31/1/37.full.pdf}, journal = {Drug Metabolism and Disposition} }