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dc.contributor.authorJuvonen, Risto O.
dc.contributor.authorHeikkinen, Aki T.
dc.contributor.authorKärkkäinen, Olli
dc.contributor.authorJehangir, Rabia
dc.contributor.authorHuuskonen, Juhani
dc.contributor.authorTroberg, Johanna
dc.contributor.authorRaunio, Hannu
dc.contributor.authorPentikäinen, Olli T.
dc.contributor.authorFinel, Moshe
dc.date.accessioned2019-11-05T13:27:12Z
dc.date.available2019-11-05T13:27:12Z
dc.date.issued2020
dc.identifier.citationJuvonen, 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. <i>European Journal of Pharmaceutical Sciences</i>, <i>141</i>, Article 105118. <a href="https://doi.org/10.1016/j.ejps.2019.105118" target="_blank">https://doi.org/10.1016/j.ejps.2019.105118</a>
dc.identifier.otherCONVID_33368498
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/66174
dc.description.abstractBeagle 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.en
dc.format.mimetypeapplication/pdf
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.relation.ispartofseriesEuropean Journal of Pharmaceutical Sciences
dc.rightsCC BY-NC-ND 4.0
dc.subject.otherglucuronidation
dc.subject.otherdog, intestine
dc.subject.otherliver
dc.subject.other7-hydroxycoumarin derivative
dc.subject.otherenzyme kinetics
dc.titleIn vitro glucuronidation of 7-hydroxycoumarin derivatives in intestine and liver microsomes of Beagle dogs
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201911054726
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.oppiaineOrgaaninen kemiafi
dc.contributor.oppiaineOrganic Chemistryen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.description.reviewstatuspeerReviewed
dc.relation.issn0928-0987
dc.relation.volume141
dc.type.versionacceptedVersion
dc.rights.copyright© 2019 Elsevier B.V.
dc.rights.accesslevelopenAccessfi
dc.subject.ysokoira
dc.subject.ysofarmakokinetiikka
dc.subject.ysokoe-eläinmallit
dc.subject.ysomaksa
dc.subject.ysolääkeaineet
dc.subject.ysoentsyymit
dc.subject.ysokumariinit
dc.subject.ysoaineenvaihdunta
dc.subject.ysosuolisto
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p5319
jyx.subject.urihttp://www.yso.fi/onto/yso/p1737
jyx.subject.urihttp://www.yso.fi/onto/yso/p28104
jyx.subject.urihttp://www.yso.fi/onto/yso/p11264
jyx.subject.urihttp://www.yso.fi/onto/yso/p1707
jyx.subject.urihttp://www.yso.fi/onto/yso/p4769
jyx.subject.urihttp://www.yso.fi/onto/yso/p19317
jyx.subject.urihttp://www.yso.fi/onto/yso/p3066
jyx.subject.urihttp://www.yso.fi/onto/yso/p10317
dc.rights.urlhttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.relation.doi10.1016/j.ejps.2019.105118
jyx.fundinginformationThis work was supported by the Academy of Finland (grant no. 137589) and by the Sigrid Juselius Foundation (grant no. 4704583).The dog samples have been provided earlier by the Roche Postdoc Fellowship (RPF) program.


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