Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms

Abstract

Although it is widely appreciated that cats respond differently to certain drugs compared with other companion animal species, the causes of these differences are poorly understood. This article evaluates published evidence for altered drug effects in cats, focusing on pharmacokinetic differences between cats, dogs, and humans, and the molecular mechanisms underlying these differences. More work is needed to better understand drug metabolism and disposition differences in cats, thereby enabling more rational prescribing of existing medications, and the development of safer drugs for this species.

Keywords: Cat; Glucuronidation; Pharmacokinetics; Species differences.

Figure 1

Pharmacokinetic evidence for differences in drug elimination rates between cats, dogs, and humans. Shown is a comparison of published elimination half-life values in cats (filled circle), dogs (open square) and humans (plus symbol) for representative drugs that are primarily eliminated by conjugation (glucuronidation, sulfation, and glycination), oxidation (CYP enzymes) or are excreted primarily unchanged into urine and/or bile. All values are expressed as a ratio of the human value. Complete pharmacokinetic data and literature references are given in Table 1 for acetylsalicylic acid, propofol, acetaminophen, carprofen and piroxicam. Because of space limitations, the references giving data for other drugs are available directly from the author.

Figure 2

Cats can readily glucuronidate salicylate, but they poorly conjugate salicylate with glycine (forming salicylurate). Shown are data from several studies comparing the urinary metabolites of salicylate when administered as the sodium salt to 7 dogs and 2 cats (one male, one female) at 44 mg / kg intravenously, or orally as acetylsalicylic acid to 25 human volunteers at a therapeutic dose of 650 mg, or to 24 human patients that had intentionally taken a moderate aspirin overdose. Data are from Davis et al (1972) for cat and dog, Chen et al (2007) for human volunteers, and Patel et al (1990) for overdose patients.

Figure 3

Proposed mechanisms for species differences in acetaminophen toxicity. Acetaminophen overdose in humans (and most other species) results in acute hepatotoxicity. The mechanism involves saturation of the detoxifying conjugation pathways (sulfation, glucuronidation, and glutathione conjugation), resulting in accumulation of the oxidative reactive metabolite N-acetyl p-quinoneimine (NAPQI) in the liver with resultant cellular damage. However in cats and dogs, acetaminophen toxicity primarily manifests as methemoglobinemia with Heinz body anemia. McConkey et al (2009) has proposed the existence of a futile cycle in erythrocytes that involves deacetylation of acetaminophen to p-aminophenol by carboxyesterases (CES) and then re-acetylation of p-aminophenol back to acetaminophen by N-acetyltransferase (NAT) isoform 2. p-aminophenol is a reactive compound that can co-oxidate with hemoglobin to form methemoglobin. Although methemoglobin can be reduced back to hemoglobin by NADH cytochrome b5 reductase, this capacity is limited. p-aminophenol is proposed to accumulate in cat and dog erythrocytes (and not in human erythrocytes) since both cat and dog (unlike human and most other species) lack NAT2. Cats may be more susceptible than dogs to this toxicity since they also lack several UGTs, including UGT1A6 and UGT1A9, which are essential for efficient elimination of acetaminophen by glucuronidation. Acetaminophen clearance is lower in cats resulting in increased levels of acetaminophen (and probably p-aminophenol).

Figure 4

Cats are sensitive to the toxic effects of acetaminophen, in part because they glucuronidate acetaminophen less efficiently than humans or dogs. Shown are data from several studies comparing the urinary metabolite profiles of acetaminophen following oral administration of a nontoxic dose of 100 mg / kg to 4 dogs, a toxic dose of 120 mg / kg to 6 cats, a therapeutic dose of 20 mg / kg to healthy human volunteers, and an intentional overdose taken by human patients. Data are from Savides et al (1984) for cat and dog, and Prescott (1980) for human volunteers and overdose patients.

Figure 5

Comparison of the size, structure, and exon content of the human, canine and feline UGT1A genes. Each gene consists of multiple exons 1 (designated UGT1A1 up to UGT1A11) each with their own promoter that are differentially spliced with the conserved exons 2 to 5. Exon 1 encodes for the UGT enzyme protein domain that binds to and determines substrate specificity, while the conserved exons code for the UDPGA binding domain shared by all UGT1A enzymes. The human gene spans 180 kilobases and contains 9 functional exons 1 that encode 9 different UGT enzymes. The canine gene is somewhat smaller (130 kilobases) but includes 10 functional exons 1, encoding 10 different UGT enzymes. However, the feline UGT1A gene is much smaller (only 40 kilobases) and has only two functional exons 1 that encode 2 different UGT enzymes. Also shown are 2 exons 1 in human and one exon 1 in cat that are considered pseudogenes (p) since they contain multiple mutations that prevent protein coding. UGT1A1 is conserved across all 3 species probably because it encodes the only known enzyme capable of high efficiency glucuronidation of bilirubin. Data are from Li and Wu (2007) for human and dog genes, or directly from the University of California at Santa Cruz genome browser for the feline gene.