In vitro glucuronidation of 7-hydroxycoumarin derivatives in intestine and liver microsomes of Beagle dogs
| Autor: | Hannu Raunio, Rabia Jehangir, Moshe Finel, Risto O. Juvonen, Olli Kärkkäinen, Olli T. Pentikäinen, Johanna Troberg, Juhani Huuskonen, Aki T. Heikkinen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
entsyymit
Colon Glucuronidation Pharmaceutical Science 02 engineering and technology liver 030226 pharmacology & pharmacy Beagle koira 7-hydroxycoumarin derivative 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Dogs Glucuronides Pharmacokinetics Microsomes enzyme kinetics Intestine Small medicine Animals Humans Umbelliferones Glucuronosyltransferase kumariinit aineenvaihdunta chemistry.chemical_classification Chemistry glucuronidation dog intestine maksa Metabolism lääkeaineet 021001 nanoscience & nanotechnology Coumarin Small intestine Enzyme medicine.anatomical_structure Biochemistry Liver farmakokinetiikka suolisto Microsome koe-eläinmallit 0210 nano-technology |
| Popis: | 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. peerReviewed |
| Databáze: | OpenAIRE |
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