Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs
Article first published online: 8 JUL 2010
© 2010 Blackwell Publishing Ltd
Journal of Veterinary Pharmacology and Therapeutics
Volume 33, Issue 6, pages 519–527, December 2010
How to Cite
Van BEUSEKOM, C. D., SCHIPPER, L. and FINK-GREMMELS, J. (2010), Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs. Journal of Veterinary Pharmacology and Therapeutics, 33: 519–527. doi: 10.1111/j.1365-2885.2010.01199.x
- Issue published online: 9 NOV 2010
- Article first published online: 8 JUL 2010
- (Paper received 11 November 2009; accepted for publication 11 February 2010)
van Beusekom, C.D., Schipper, L., Fink-Gremmels, J. Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs. J. vet. Pharmacol. Therap. 33, 519–527.
This study aimed to investigate the biotransformation of cat liver microsomes in comparison to dogs and humans using a high throughput method with fluorescent substrates and classical inhibitors specific for certain isozymes of the human cytochrome P450 (CYP) enzyme family. The metabolic activities associated with CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A were measured. Cat liver microsomes metabolized all substrates selected for the assessment of cytochrome P450 activity. The activities associated with CYP3A and CYP2B were higher than the activities of the other measured CYPs. Substrate selectivity could be demonstrated by inhibition studies with α-naphthoflavone (CYP1A), tranylcypromine/quercetine (CYP2C), quinidine (CYP2D), diethyldithiocarbamic acid (CYP2E) and ketoconazole (CYP3A) respectively. Other prototypical inhibitors used for characterization of human CYP activities such as furafylline (CYP1A), tranylcypromine (CYP2B) and sulfaphenazole (CYP2C) did not show significant effects in cat and dog liver microsomes. Moreover, IC50-values of cat CYPs differed from dog and human CYPs underlining the interspecies differences. Gender differences were observed in the oxidation of 7-ethoxy-4-trifluoromethylcoumarin (CYP2B) and 3-[2-(N, N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D), which were significantly higher in male cats than in females. Conversely, oxidation of the substrates dibenzylfluorescein (CYP2C) and 7-methoxy-4-trifluoromethylcoumarin (CYP2E) showed significant higher activities in females than in male cats. Overall CYP-activities in cat liver microsomes were lower than in those from dogs or humans, except for CYP2B. The presented difference between feline and canine CYP-activities are useful to establish dose corrections for feline patients of intensively metabolized drugs licensed for dogs or humans.