A1 Journal article (refereed)
In vitro glucuronidation of 7-hydroxycoumarin derivatives in intestine and liver microsomes of Beagle dogs (2020)

Juvonen, R. O., Heikkinen, A. T., Kärkkäinen, O., Jehangir, R., Huuskonen, J., Troberg, J., Raunio, H., Pentikäinen, O. T., & Finel, M. (2020). In vitro glucuronidation of 7-hydroxycoumarin derivatives in intestine and liver microsomes of Beagle dogs. European Journal of Pharmaceutical Sciences, 141, Article 105118. https://doi.org/10.1016/j.ejps.2019.105118

JYU authors or editors

Publication details

All authors or editors: Juvonen, Risto O.; Heikkinen, Aki T.; Kärkkäinen, Olli; Jehangir, Rabia; Huuskonen, Juhani; Troberg, Johanna; Raunio, Hannu; Pentikäinen, Olli T.; Finel, Moshe

Journal or series: European Journal of Pharmaceutical Sciences

ISSN: 0928-0987

eISSN: 1879-0720

Publication year: 2020

Volume: 141

Article number: 105118

Publisher: Elsevier BV

Publication country: Netherlands

Publication language: English

DOI: https://doi.org/10.1016/j.ejps.2019.105118

Publication open access: Not open

Publication channel open access: 

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/66174

Abstract

Beagle dog is a standard animal model for evaluating nonclinical pharmacokinetics of new drug candidates. Glucuronidation in intestine and liver is an important first-pass drug metabolic pathway, especially for phenolic compounds. This study evaluated the glucuronidation characteristics of several 7-hydroxycoumarin derivatives in beagle dog's intestine and liver in vitro. To this end, glucuronidation rates of 7-hydroxycoumarin (compound 1), 7-hydroxy-4-trifluoromethylcoumarin (2), 6-methoxy-7-hydroxycoumarin (3), 7-hydroxy-3-(4-tolyl)coumarin (4), 3-(4-fluorophenyl)coumarin (5), 7-hydroxy-3-(4-hydroxyphenyl)coumarin (6), 7-hydroxy-3-(4-methoxyphenyl)coumarin (7), and 7-hydroxy-3-(1H-1,2,4-tirazole)coumarin (8) were determined in dog's intestine and liver microsomes, as well as recombinant dog UGT1A enzymes. The glucuronidation rates of 1, 2 and 3 were 3–10 times higher in liver than in small intestine microsomes, whereas glucuronidation rates of 5, 6, 7 and 8 were similar in microsomes from both tissues. In the colon, glucuronidation of 1 and 2 was 3–5 times faster than in small intestine. dUGT1A11 glucuronidated efficiently all the substrates and was more efficient catalyst for 8 than any other dUGT1A. Other active enzymes were dUGT1A2 that glucuronidated efficiently 2, 3, 4, 5, 6 and 7, while dUGT1A10 glucuronidated efficiently 1, 2, 3, 4, 5 and 7. Kinetic analyses revealed that the compounds’ Km values varied between 1.1 (dUGT1A10 and 2) and 250 µM (dUGT1A7 and 4). The results further strengthen the concept that dog intestine has high capacity for glucuronidation, and that different dUGT1As mediate glucuronidation with distinct substrates selectivity in dog and human.

Keywords: medicinal substances; coumarins; metabolism; enzymes; intestines; liver; pharmacokinetics; animal disease models; dog

Free keywords: glucuronidation; dog, intestine; liver; 7-hydroxycoumarin derivative; enzyme kinetics

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2020

JUFO rating: 2