Enzyme-assisted synthesis and structure characterization of glucuronic acid conjugates of losartan, candesartan, and zolarsartan |
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Authors: | Alonen Anna Jansson Johanna Kallonen Sirkku Kiriazis Alexandros Aitio Olli Finel Moshe Kostiainen Risto |
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Affiliation: | aFaculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FIN 00014, Finland;bProgram in Structural Biology and Biophysics, Institute of Biotechnology, NMR Laboratory, University of Helsinki, P.O. Box 56 (Viikinkaari 9), FIN 00014, Finland;cFaculty of Pharmacy, Drug Discovery and Development Technology Center, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FIN 00014, Finland |
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Abstract: | Three angiotensin II receptor antagonists—losartan, candesartan, and zolarsartan—were investigated. All the compounds, which are structural analogues, are metabolized via conjugation to glucuronic acid. Interestingly, both O- and N-glucuronidation take place, so that regioisomers are formed. One ether O-glucuronide, two acyl O-glucuronides, and five tetrazole-N-glucuronides were biosynthesized, in milligram scale, from the three sartan aglycones. Liver microsomes from bovine, moose, rat, and pig and recombinant human UDP-glucuronosyltransferases were used as catalysts. The synthesized compounds were identified as sartan glucuronides by mass spectrometry, while the sites of glucuronidation were determined by nuclear magnetic resonance spectroscopy. Drug metabolites are needed as standards for pharmaceutical research and, as the present study shows, they can easily be produced with enzymes as catalyst. |
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Keywords: | Losartan Candesartan Zolarsartan GR117289 Glucuronide Biosynthesis Regioisomer |
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