PHARMACOKINETICS

Pharmacokinetics plays an important role in carprofen toxicosis. Nearly 90% to 100% of the ingested drug is bioavailable,¹⁸ with a peak plasma concentration in one to three hours.^2,19 Carprofen is also highly protein-bound, which can exacerbate the toxic effects of coadministered drugs that are also highly protein-bound, particularly drugs with a narrow margin of safety (e.g. anticoagulants, digoxin, methotrexate) as well as in dogs in which hepatic function may be abnormal.^2,13 In dogs, the elimination half-life ranges from eight to 18 hours^2,4,19; 70% to 80% of carprofen is metabolized by direct conjugation to an ester glucuronide followed by oxidation to phenol and further conjugation. These conjugated phenols are eliminated in the feces. Smaller amounts of carprofen are excreted as hydroxy metabolites in urine.^2,20 Enterohepatic circulation has been documented for carprofen.¹⁹

Because of cats' limited ability to metabolize carprofen via glucuronidation, the drug's elimination half-life (20.1 ± 16.6 hours)²¹ in that species is longer than in dogs. Consequently, use of the drug in cats poses a far greater risk of adverse effects. In the United States, carprofen use in cats remains extralabel, so the pharmacokinetic differences in this species should be kept in mind, and extreme caution should be exercised when administering carprofen in cats.

Because of dogs' relative lack of dietary discretion and the palatability of chewable Rimadyl tablets, it is not unusual for a dog to ingest an entire bottle of carprofen tablets if it is accessible (ASPCA APCC Database: Unpublished data, 2001-2009). With a maximum of 240 caplets per bottle and 100 mg per tablet,³ extreme ingestions are possible. And given the narrow margin of safety in cats, ingesting just one 25-mg tablet is potentially serious.

TABLE 1: Clinical Signs Associated with Acute Carprofen Toxicosis in Dogs

TABLE 2: Clinical Signs Associated with Acute Carprofen Toxicosis in Cats

In otherwise healthy dogs, a review of the ASPCA APCC database historically indicated that fairly severe gastrointestinal signs may be seen at doses exceeding 20 mg/kg and that diuresis to prevent renal damage should be recommended at 40 mg/kg and above (ASPCA APCC Database: Unpublished data, 2001-2009).

Hepatic damage may occur with any dose, but the potential for nonidiosyncratic damage, by definition, should worsen with increased doses. According to the ASPCA APCC database, mild, transient, and often subclinical elevations of alanine transaminase (ALT) and alkaline phosphatase (ALP) activities have been seen with single, acute exposures beginning in the 40-mg/kg range in dogs. With single, acute exposures exceeding 100 mg/kg in dogs, more moderate to severe elevations in ALT and ALP activities can be seen, and these are often associated with clinical illness. Prophylactic administration of s-adenosylmethionine (SAMe) (17 to 20 mg/kg or more per day on an empty stomach) is recommended in dogs at greater risk for hepatic damage. A similar trend has not been identified in cats, but prophylactic SAMe administration (200 mg/kg on an empty stomach) should be considered in cats as well.

Neurologic signs, including seizures, stupor, and coma, tend to be seen with extreme ingestions. Respectively, these signs have been seen in ASPCA APCC cases in carprofen ingestions of 281, 536, and 645 mg/kg in dogs. Death despite treatment has been reported at 536 mg/kg. Definitive damage to the kidneys, as evidenced by the presence of urinary casts, was seen in a dog that ingested 48 mg/kg of carprofen.

In cats, the ASPCA APCC data indicate that ingestions of 4 mg/kg and above would be expected to cause more than mild gastrointestinal signs, and ingestions of 8 mg/kg and above may result in acute renal failure (ASPCA APCC Database: Unpublished data, 2001-2009). One 3-month-old kitten received 8.6 mg/kg of carprofen orally and was euthanized after acute renal failure developed. The lowest reported dose for death in a cat was ingestion of a possible range of 27.5 to 45.8 mg/kg (ASPCA APCC Database: Unpublished data, 2001-2009).

For both dogs and cats, keep in mind this information is from cases in which medical intervention had been sought and may not reflect the lowest doses at which signs may arise in untreated animals. Furthermore, because complete clinical findings and case outcomes are not always reported to the ASPCA APCC and because not all dosages are represented in the exposures reported, the lowest reported dosage at which a specific adverse effect has been seen may not be the true lowest dosage at which that effect is possible.