A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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-tekijät tai -toimittajat
Julkaisun tiedot
Julkaisun kaikki tekijät tai toimittajat: Juvonen, Risto O.; Heikkinen, Aki T.; Kärkkäinen, Olli; Jehangir, Rabia; Huuskonen, Juhani; Troberg, Johanna; Raunio, Hannu; Pentikäinen, Olli T.; Finel, Moshe
Lehti tai sarja: European Journal of Pharmaceutical Sciences
ISSN: 0928-0987
eISSN: 1879-0720
Julkaisuvuosi: 2020
Volyymi: 141
Artikkelinumero: 105118
Kustantaja: Elsevier BV
Julkaisumaa: Alankomaat
Julkaisun kieli: englanti
DOI: https://doi.org/10.1016/j.ejps.2019.105118
Julkaisun avoin saatavuus: Ei avoin
Julkaisukanavan avoin saatavuus:
Julkaisu on rinnakkaistallennettu (JYX): https://jyx.jyu.fi/handle/123456789/66174
Tiivistelmä
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.
YSO-asiasanat: lääkeaineet; kumariinit; aineenvaihdunta; entsyymit; suolisto; maksa; farmakokinetiikka; koe-eläinmallit; koira
Vapaat asiasanat: glucuronidation; dog, intestine; liver; 7-hydroxycoumarin derivative; enzyme kinetics
Liittyvät organisaatiot
OKM-raportointi: Kyllä
Raportointivuosi: 2020
JUFO-taso: 2
