Metabolic Differences

Cats have important differences in drug biotransformation compared to humans and dogs. It is well known that cats are deficient in glucuronidation of some xenobiotics; for example, UDP-glucuronosyltransferase (UGT) activity, for acetaminophen is 10- fold lower in cats compared to dogs and humans. This is due to a nonfunctional feline pseudogene for UGT1A6, the enzyme that metabolizes acetaminophen in humans. This same enzyme appears to metabolize aspirin and Silybin (in milk thistle). Cats show impaired clearance of several glucuronidated drugs, to include aspirin (dosed ¼ as frequently in cats), chloramphenicol, and carprofen (20-hour half-life in cats; GI toxicity at 2- to 3-fold lower doses than in dogs).

Cats are also deficient in the enzyme thiopurine methyltransferase (TPMT), which is important for azathioprine metabolism. TPMT activity, which can be measured in red blood cells, is 80–85% lower in cats compared to dogs. This is probably why cats treated with azathioprine are especially sensitive to myelosuppression, which is a dose-dependent side effect. Further individual variability in thiopurine methyltransferase among cats (almost 10-fold) can be attributed to genetic polymorphisms in the feline gene, such that there is overlap between some "high activity" cats and some "low activity" dogs. However, we have not been able to establish a relationship between polymorphisms in TPMT and azathioprine response in either cats or dogs.

Drug Dosing in Cats with Renal Insufficiency

Renal failure leads to decreased filtration of renally eliminated drugs and their active metabolites, as well as impaired tubular secretion of some drugs, to include famotidine, ranitidine, trimethoprim, and digoxin. Dosage reductions in renal failure are indicated for any drug with a relatively narrow margin of safety for which the parent drug or an active metabolite is either primarily eliminated by the kidneys. There is little information in cats to guide dosage adjustments for renal failure. In humans, dose adjustments are typically made when glomerular filtration (GFR), as measured by creatinine clearance, drops to about 0.7–1.2 ml/kg/min, depending on the drug's therapeutic index. Based on the demonstrated relationship between GFR and serum creatinine in cats, this is equivalent to serum creatinine concentrations of approximately 2.5 to 3.5 mg/dl (221–309 micromoles/L). In the absence of specific data in cats, it is reasonable to consider dosage adjustments for renally cleared drugs when the serum creatinine reaches this range. Dosage adjustments can be made by reducing the individual dose and/or by giving the same dose less frequently (see Table 1 for recommendations).

Two drugs for which an extended dosing interval is recommended are aminoglycosides and fluoroquinolones. Aminoglycosides are dose-dependent nephrotoxins and should be avoided in preexisting renal disease. For a patient with renal insufficiency and a resistant Gram-negative infection, other antimicrobials (such as marbofloxacin, cefotetan, meropenem, or ticarcillin) should be considered whenever possible. When aminoglycosides are necessary, rehydration and concurrent fluid therapy (IV or SC) are recommended, since hypovolemia is a risk factor for aminoglycoside nephrotoxicity in humans. These drugs are concentration-dependent antimicrobials (i.e., bacterial kill correlates with peak concentrations, not time above the MIC), and nephrotoxicity correlates with trough, not peak, drug concentrations. Therefore, aminoglycosides should be given at the same dose, but less frequently, in renal failure. One practical way to monitor for early nephrotoxicity is to examine daily fresh urine sediments for granular casts, which can be seen days before azotemia develops from aminoglycosides, and suggest that the drug should be discontinued, unless the infection is life-threatening. Toxicity in cats is lessened if aminoglycoside therapy can be limited to 5 days or less, whenever possible. Aminoglycosides are contraindicated in combination with furosemide or NSAIDs - each of which can exacerbate nephrotoxicity.

Fluoroquinolones, like aminoglycosides, are renally cleared. Although they do not cause cartilage toxicity in growing kittens at the label dosage, they do cause dose-dependent retinal toxicity in cats. Therefore, dosage adjustments for fluoroquinolones may be important in cats with renal insufficiency, although this has not been directly evaluated. Dosage adjustments may be particularly important for enrofloxacin, which appears to be more retinotoxic in cats (retinal lesions at 4 times the label dosage) compared to other veterinary fluoroquinolones (orbifloxacin, retinal lesions at 18 times the label dose; marbofloxacin, no retinal lesions at 20 times the label dose). Although the optimal method for dose adjustment is not established in cats, extending the dosing interval may be most appropriate, since fluoroquinolones are also concentration-dependent.

Drug Therapy in Hepatic Insufficiency

In humans with inflammatory liver diseases, hepatic drug metabolism appears to be fairly well conserved. With cirrhosis or hepatic failure, however, humans show impaired clearance of some drugs, to include buspirone, butorphanol, cyclophosphamide, cisapride, diazepam, doxorubicin, fluoxetine, loratadine, metronidazole, midazolam, mirtazapine, omeprazole, prednisolone, propranolol, theophylline, and vincristine. For these drugs, dosage reductions, to 25–50% of regular dosages, are recommended. Although cirrhosis is uncommon in cats, comparable hepatic dysfunction is common in cats with fulminant hepatic lipidosis or portosystemic shunts.

Table 1. Recommendations for drug dosage adjustment in renal failure, extrapolated from human studies and adapted from expert opinion

From: Margo Karriker, PharmD, Advanced Renal Therapies Symposium, 2006.