Enzyme-assisted synthesis and structure characterization of glucuronic acid conjugates of losartan, candesartan, and zolarsartan.
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.
Alonen
Anna
A
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, PO Box 56 (Viikinkaari 5 E), FIN 00014, Finland.
Jansson
Johanna
J
Kallonen
Sirkku
S
Kiriazis
Alexandros
A
Aitio
Olli
O
Finel
Moshe
M
Kostiainen
Risto
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002417:Cattle; D003670:Deer; D020723:Glucuronic Acid; D020719:Glucuronides / Q000138:chemical synthesis / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D019808:Losartan; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D013552:Swine; D013777:Tetrazoles
D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D020719:Glucuronides; D013777:Tetrazoles; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase; D019808:Losartan; C081643:candesartan