Comparing the glucuronidation capacity of the feline liver with substrate‐specific glucuronidation in dogs

Abstract

This study aimed to assess the overall glucuronidation capacity of cats, using prototypic substrates identified for human UDP-glucuronosyltransferases (UGTs). To this end, Michaelis-Menten kinetics were established for the substrates using feline hepatic microsomal fractions, and results were compared with similar experiments carried out with dog liver microsomes. Cats are known for their low capacity of glucuronide formation, and UGT1A6 was found to be a pseudogene. However, functional studies with typical substrates were not performed and knowledge of the enzymology and genetics of other glucuronidation enzymes in felidae is lacking. The results of this study showed extremely low formation of naphthol-1-glucuronide (1.7 ± 0.4 nmol/mg protein/min), estradiol-17-glucuronide (<0.7 nmol/mg protein/min), and morphine-3-glucuronide (0.2 ± 0.03 nmol/mg protein/min), suggesting a lack of functional UGT1A6 and UGT2B7 homologues in the cat's liver. Dog liver microsomes were producing these glucuronides in much higher amounts. Glucuronide capacity was present for the substrates 17β-estradiol (estradiol-3-glucuronide, 2.9 ± 0.2 nmol/mg protein/min) and 4-methylumbelliferone (31.3 ± 3.3 nmol/mg protein/min), assuming that cats have functional homologue enzymes to at least the human UGT1A1 and probably other UGT1A isozymes. This implies that for new drugs, glucuronidation capacity has to be investigated on a substance-to-substance base. Knowledge of the glucuronidation rate of a drug provides the basis for pharmacokinetic modeling and as a result proper dosage regimens can be established to avoid undesirable drug toxicity in cats.

Pharmacokinetics of liposomal encapsulated buprenorphine suspension following subcutaneous administration to cats

“…Although no studies evaluating the metabolism and biliary excretion of buprenorphine and metabolites in cats have been published to our knowledge, it is conceivable that our cats excreted bile containing sizable amounts of unchanged buprenorphine at times corresponding to their ad libitum feeding. In this regard, cats have a very low capacity to glucuronate the phenolic moieties of morphine and other opioids (van Beusekom et al ., ), and buprenorphine glucuronide is the major metabolite found in the bile of dogs (Garrett & Chandran, ) and rats (Ohtani et al ., ). The plasma buprenorphine concentrations recorded by beyond 4 h following the i.v.…”

Feline biliary tree and gallbladder disease: Aetiology, diagnosis and treatment

“…7 Felids have a low capacity for glucuronide conjugation of drugs and toxins, limiting their conversion to water-soluble substances that can be excreted into urine or bile. 13 This makes cats more prone to suffer hepatotoxic effects when exposed to certain drugs and toxins (see box above for commonly used drugs that are hepatotoxic to cats).…”

Cats, Cancer and Comparative Oncology

“…In terms of using cats as pre-clinical models for assessment of new drugs, thorough consideration needs to be given to drug metabolism and pharmacokinetics in this species before determination of applicability in people can be made. Cats are known to have reduced overall hepatic glucuronidation capacity compared to dogs and humans, though this seems to be drug-specific [ 26 , 27 ]. Consideration of metabolic pathways prior to clinical trials of potential new drugs in cats is recommended.…”