Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs

Abstract

-Gremmels, J. Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs. J. vet. Pharmacol. Therap. 33,[519][520][521][522][523][524][525][526][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 a-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.

A Remote Assay for Measuring Canine Platelet Activation and the Inhibitory Effects of Antiplatelet Agents

“…Dogs receiving clopidogrel and omeprazole had increased concentrations of clopidogrel inactive metabolites although this did not alter platelet activity . The influence of genetic polymorphisms in dogs remains unclear as variations in cytochrome P450‐metabolic activity exist between humans, dogs, and cats . P2Y 12 polymorphisms, which do not cause spontaneous hemorrhage, can still alter the response to medications .…”

Pharmacogenetics of opioid analgesics in dogs

“…Biotransformation converts any drug to its metabolite/s which are less or more active than their parent compound and ultimately aids in drug elimination from the body (Beusekom, Schipper, & Fink-Gremmels, 2010). Nearly 50%-60% of all medications including anaesthetic and analgesic drugs are metabolized by the cytochrome P450 (CYP 450) enzymes via phase I reactions.…”

“…Nearly 50%–60% of all medications including anaesthetic and analgesic drugs are metabolized by the cytochrome P450 (CYP 450) enzymes via phase I reactions. Phase I pathways include the drug oxidation, reduction, hydrolysis and hydroxylation (Beusekom et al., ). Phase II metabolizing enzymes conjugate phase I metabolites, or the parent compound for excretion via the kidney or bile.…”

Altered hepatic cytochrome P450 expression in cats after chronic exposure to decabromodiphenyl ether (BDE-209)

“…We recently reported that CYP3A is dominant subfamily in the liver [16] and it could play a major role in hepatic xenobiotic metabolism for cats [15,16]. However, the liver microsome in cats revealed lower CYP3A activity than in humans and dogs and the relationship between molecular structure and metabolic activity is still largely unknown in cats [39]. Thus, the studies on feline CYP3A activity and the selectivity of CYP3A for BDE-209 metabolism are also necessary.…”