Although it is widely appreciated that cats respond differently to certain drugs when compared with other companion animal species, the causes of these differences are poorly understood. This lecture will critically evaluate evidence for altered drugeffects in cats, focusing on pharmacokinetic differences between cats, dogs and humans, and the molecular mechanisms underlying these differences.A review of published pharmacokinetic studies' indicate that acetaminophen, propofol, carprofen, and acetylsalicylic acid (aspirin) are cleared significantly more slowly in cats versus dogs and humans (Figure 1). All of these drugs are metabolized by conjugation. Cats lack the major phenol UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6 and UGT1A9, that glucuronidate acetaminophen and propofol (Figure 2a). Deficient glucuronidation may also explain slower carprofen clearance, although thereis no direct evidence for this. Table 1 lists drugs with direct evidence that they are glucuronidated more slowly, or with similar efficiency compared with most other mammalian species. Although pharmacology textbooks commonly state that sensitivity of cats to the effects of aspirin (and related salicylates) is a consequence of poor glucuronidation by cats, there is no evidence to support this. In fact, the main pathway for elimination of aspirin (and other salicylates) in most species is glycine conjugation of the salicylate to form salicylurate that is excreted in urine4. As shown in Figure 2b, cats readily excrete salicylate glucuronides in the urine but poorly eliminate salicylurate suggesting a deficiency in glycine conjugation. Cats are also deficient in several other conjugation enzymes, including N-acetyltransferase (NAT) 2 and thiopurine methyltransferase (TMPT)6'7. NAT2 deficiency may be the reason cats are more prone to developing methemoglobinemia rather than hepatotoxicity from acetaminophen8. TMPT deficiency may predispose cats to azathioprine toxicity. No evidence was found for slower elimination of drugs cleared by oxidation or unchanged into urine or bile. Piroxicam, an oxidized drug, was cleared much more rapidly in cats than humans and dogs, although the mechanism for this difference is unclear.
展开▼
