title: In vitro glucuronidation of the angiotensin II receptor antagonist telmisartan in the cat: a comparison with other species.
abstract: Glucuronidation of telmisartan comprises nearly its entire metabolic clearance in several mammalian species including human. However, data were lacking for the cat, a species noted for its inability to glucuronidate some drugs. Therefore, the glucuronidation of telmisartan was investigated using feline liver microsomes and compared to liver microsomes of rats, dogs, and human, intestinal human microsomes and cell lines expressing human UDP-glucuronosyltransferases (UGT). Incubation of telmisartan with cat liver microsomes readily yielded telmisartan glucuronide, and pooled (N = 3 for each gender) cat liver microsomes even showed the highest glucuronidation rate (cat > dog >> human > rat). Michaelis Menten kinetics were observed with Km of 7.5 and 10 μm and Vmax of 3.9 and 3.3 nmol/min/mg for male and female cats, respectively. Confirming the in vitro data, telmisartan glucuronide was detected as the major circulating metabolite in cat plasma. To elucidate which UGT enzymes are involved, telmisartan was incubated with cell lines expressing human UGTs. The highest glucuronidation activity was observed for UGT1A8, UGT1A7, and UGT1A9. In conclusion, telmisartan was effectively glucuronidated in cats. Defects of the UGT1A6 gene in cats do not affect the glucuronidation of telmisartan as it is not a substrate of human UGT1A6.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany. thomas.ebner@boehringer-ingelheim.com
authors.forename: T
authors.initials: T
authors.lastname: Ebner
authors.forename: G
authors.initials: G
authors.lastname: Schänzle
authors.forename: W
authors.initials: W
authors.lastname: Weber
authors.forename: U
authors.initials: U
authors.lastname: Sent
authors.forename: J
authors.initials: J
authors.lastname: Elliott
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism*; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism*; D002415:Cats / Q000097:blood / Q000378:metabolism*; D004285:Dogs; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013045:Species Specificity; D000077333:Telmisartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D014453:Glucuronosyltransferase; D000077333:Telmisartan