Page 392 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicity of Over-the-Counter Drugs Chapter | 21 359

VetBooks.ir liver. There are three major pathways: direct glucuronide excreted predominantly through the urine (MacNaughton,
The byproducts of acetaminophen metabolism are
Metabolism of acetaminophen occurs primarily in the
conjugation, direct sulfate conjugation, and oxidation
2003; Sellon, 2006; Sturgill and Lambert, 1997). Less
mediated by cytochrome P450 enzymes (Hjelle and Grauer, than 5% of a dose is excreted as the parent compound in
1986; Wallace et al., 2002). Acetaminophen has an avail- humans (Wallace et al., 2002), and some conjugates are
able hydroxyl group. Immediate phase II conjugation is the eliminated in the bile (Sturgill and Lambert, 1997;
primary route of metabolism in most species, and involves Maddrey, 2005). The rate of elimination is dependent
glucuronide and sulfate (Dahm and Jones, 1996). Due to upon the species and the dose. The elimination half-life of
limitations of cat physiology, they have only about one- a 100 200 mg/kg dose of acetaminophen is 72 min in
tenth the acetaminophen biotransformation ability of dogs dogs, and increases to 210 min when the dose is increased
(Hjelle and Grauer, 1986; Sellon, 2006). Glucuronide conju- to 500 mg/kg. The elimination half-life in cats for a
gation is the fate of 50% 60% of a dose of acetaminophen 20 mg/kg, dose is 36 min, but increases to 144 min and
given to either a human or dog (Aronson and Drobatz, 288 min for a 60 mg/kg and a 120 mg/kg dose, respec-
1996); this pathway is deficient in cats due to decreased tively (Hjelle and Grauer, 1986). The half-life is longer in
microsomal UDP-glucuronosyltransferase enzyme activity male cats compared to females (Rumbeiha et al., 1995).
(Wallace et al., 2002).
The amount of acetaminophen that is conjugated to
glucuronide in cats is dependent upon dose, but is always Mechanism of Action
a relatively small proportion. After an oral dose of 20, Unlike NSAIDs, the therapeutic effects of acetaminophen
60, and 120 mg/kg acetaminophen, only 1%, 5%, and are independent of cyclooxygenase (COX), and are based
16% undergo glucuronide conjugation, respectively on interference with endoperoxidase (Boothe, 2001). A
(Hjelle and Grauer, 1986). Sulfate conjugation is less new isoenzyme of COX, however, COX3, has been iden-
important than glucuronide conjugation in the disposition tified in dogs, and is reported to be a target of acetamino-
of acetaminophen in most species aside from cats phen. COX3 could be responsible for decreased tear
(Aronson and Drobatz, 1996; Boothe, 2001; Allen, production in acetaminophen-induced keratoconjunctivitis
2003). Dogs metabolize only about 10% 20% of a given sicca (Stewart et al., 2016). The main target organ for
dose of acetaminophen via sulfate conjugation. Again, acetaminophen in most species is the liver. The hepato-
use of this pathway is dependent upon the dose of acet- toxic effects of acetaminophen are due primarily to the
aminophen. After cats were dosed with 20 mg, 60 mg, metabolite NAPQI. Large doses of acetaminophen over-
and 120 mg acetaminophen/kg, 92%, 78%, and 57% of whelm the sulfide and glucuronide conjugation pathways
the acetaminophen underwent sulfate conjugation, and lead to increased formation of active metabolite
respectively. The sulfate conjugation pathway can be sat- (Hjelle and Grauer, 1986; Dahm and Jones, 1996; Sturgill
urated due to the limited availability of inorganic sulfates and Lambert, 1997; MacNaughton, 2003; Roder, 2004a).
(Hjelle and Grauer, 1986). NAPQI is usually conjugated with GSH, as noted above.
Metabolism of acetaminophen by phase I processes is GSH stores become depleted 16 24 h after exposure to
relatively minimal in most species, but is very important acetaminophen.
to the mechanism of toxicity of this drug, as will be Hepatotoxic effects predominate in dogs, mice, rats,
described later. Cytochrome P450 oxidation increases as and humans, and occur in dogs and cats (Wallace et al.,
phase II pathways become saturated (MacNaughton, 2002; Sellon, 2006). Oxidative damage to hepatocytes
2003; Sellon, 2006). Approximately 5% of a dose of acet- leads to zone 3 (centrilobular) hepatocyte degeneration
aminophen undergoes oxidation by cytochrome P450s in and necrosis (Hjelle and Grauer, 1986; Dahm and Jones,
dogs. When cats are dosed with 20 mg/kg acetaminophen, 1996; Treinen-Moslen, 2001; Wallace et al., 2002).
5% undergoes oxidation, but this number increased to NAPQI acts as an electrophile, causing tissue damage
10% at doses of 60 120 mg/kg (Hjelle and Grauer, through formation of covalent adducts with biological
1986). The product of the oxidation pathway is N-acetyl macromolecules (Savides and Oehme, 1985; Hjelle and
benzoquinoneimine (NAPQI). NAPQI is conjugated to Grauer, 1986; Jones et al., 1992; Dahm and Jones, 1996;
reduced glutathione (GSH), forming an inactive product. Sturgill and Lambert, 1997; Villar et al., 1998;
A second byproduct of acetaminophen metabolism, via Zimmerman, 1999; Treinen-Moslen, 2001). NAPQI inter-
phase I deacetylation, is para-aminophenol (PAP), which acts with cysteine residues on mitochondrial proteins,
is of importance to the mechanism of toxicity in dogs and leading to mitochondrial dysfunction and adenosine tri-
cats. PAP is rapidly conjugated to GSH or acetate in phosphate (ATP) depletion (Khayyat et al., 2016). NAPQI
laboratory rodents, but cats have reduced capacity for is also believed to bind to membrane proteins that regu-
N-acetylation and dogs lack the hepatic N-acetyltransfer- late calcium homeostasis, thus increasing intracellular cal-
ase enzyme (McConkey et al., 2009). cium concentrations. Cytoskeletal damage/activation of