Page 398 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicity of Over-the-Counter Drugs Chapter | 21 365

VetBooks.ir et al., 1991; Boothe, 2001), and blood concentrations are (Runkel et al., 1972). Drugs eliminated in the bile, such
as ibuprofen and naproxen, as well as carprofen, indo-
almost identical whether dosing is PO or IV (Runkel
methacin, piroxicam, flunixin, tolfenamic acid, meclofe-
et al., 1972). Naproxen is 50% bioavailable in horses
(Boothe, 2001) and nearly 100% bioavailable in pigs namic acid, and diclofenac, undergo enterohepatic
(Runkel et al., 1972). circulation in dogs. This prolongs the plasma half-life,
NSAID distribution is variable between individual and is likely the cause of increased susceptibility of dogs
drugs and animal species. Because they are highly to these compounds.
protein-bound in the circulation, mostly to albumin, The plasma half-life of ibuprofen is 2.5 6 h in dogs
NSAIDs generally have a low volume of distribution and cats and 1 h in rats (Mazue ´ et al., 1982; Lees et al.,
(Brater, 1988; Verbeeck, 1990; Boothe, 2001; Talcott, 1991; Boothe, 2001). The half-life for naproxen in plasma
2006). Protein binding in humans is 99% for ibuprofen is 35 h in beagles (Runkel et al., 1972), 74 h in mixed-
(Brater, 1988), .99% for naproxen (Runkel et al., 1972; breed dogs (Isaacs, 1996), 5 h in h (Lees et al., 1991;
Rubin and Papich, 1990), and 98.7% for ketoprofen Isaacs, 1996), 4.8 h in cows (Lees et al., 1991), 4.8 h in
(Brater, 1988). The remaining unbound fraction becomes minipigs, 1.9 h in rhesus monkeys, and 8.7 h in guinea
distributed in the extracellular fluid and is responsible for pigs. Elimination of phenylbutazone in dogs appears to
the clinical effects (Brater, 1988; Kore, 1990; Boothe, follow zero-order kinetics (Lees et al., 1991). The plasma
2001; Talcott, 2006). Hypoalbuminemia or displacement half-life for phenylbutazone is between 5 and 8 h in
from protein-binding sites by other drugs leads to a tran- horses, 37 h in cattle, and 4 h in swine.
sient increase in the unbound fraction. Although this
unbound drug is normally rapidly excreted, clinical
effects can be evident. NSAIDs can partition into lipid, Mechanism of Action
allowing them to cross cell membranes. The basic mechanism of action of NSAIDs is inhibition
Metabolism of NSAIDs takes place primarily in the of COX enzymes. These enzymes are found in all cells
liver. Most undergo cytochrome P450-mediated oxidation except mature erythrocytes (Kore, 1990; Boothe, 2001).
to increase water solubility. Phenylbutazone is converted Arachidonic acid, a 20-carbon unsaturated fatty acid, is
to oxyphenbutazone, which is similarly potent, via phase I released from the cell membrane by phospholipase A 2
hepatic metabolism (Lees et al., 1991). Phase I metabo- and phospholipase C when a cell is damaged. Carprofen
lites and, in the case of carboxylic acid-group NSAIDs, causes moderate inhibition of these phospholipases (Lees
the parent compound can undergo phase II reactions such et al., 1991; McKellar et al., 1991). Although arachidonic
as glucuronide conjugation, sulfate conjugation, and glu- acid itself has little activity, it can enter two pathways:
tathione conjugation, which further increase water solubil- the COX pathway, which produces eicosanoids, or the
ity and usually inactivate the drug. Acyl-glucuronide lipoxygenase pathway, which produces leukotrienes
conjugation of propionic acid NSAIDs such as ibuprofen (LTs). Oxidation of arachidonic acid by COX, and further
and naproxen is reversible, and these drugs deconjugate if metabolism by other enzymes, leads to the production
excretion is delayed. of various PGs and the release of oxygen-free radicals
Drug elimination is dependent upon compound and (Lees et al., 1991; Boynton et al., 1998). These PGs
animal species. Animals younger than 6 weeks old, as include PGH 2 , PGE 2 , and PGI 2 . With the addition of pros-
well as geriatric animals, usually metabolize drugs tacyclin synthase, PGF 2 α is formed; thromboxane
slower; hepatic or renal failure further delays elimination. synthase is needed for production of thromboxane A 2 .
High plasma protein binding also slows excretion. Plasma PGE 2 and PGI 2 have similar actions, although the
clearance is biphasic, with a rapid initial decline as the effects of PGI 2 tend to be of shorter duration. PGE 2 ,
drug is distributed to the tissues, and then a slower decline which is secreted by the gastrointestinal mucosa and at
as it is metabolized and excreted, terminating drug other sites, causes smooth muscle relaxation and vasodila-
activity (Lees et al., 1991). Less than 1% of a dose of tion, which enhances blood flow to the kidneys and gas-
naproxen or ketoprofen is eliminated unchanged, and tric mucosa and increases vascular permeability. It
approximately 1% of a given dose of ibuprofen is inhibits gastric acid production, inhibits pepsin produc-
excreted in the urine as the parent compound (Brater, tion, increases gastric mucus synthesis, and is believed to
1988). Urinary excretion is pH-dependent, and tends to be mediate repair and turnover of gastric epithelium (Collins
more rapid in alkali urine due to ion trapping. and Tyler, 1985; Boynton et al., 1988; Wallace et al.,
Fecal elimination through biliary excretion is impor- 1990). PGE 2 is also found in inflammatory exudate and
tant for ibuprofen, naproxen, and carprofen in dogs enhances pain response due to bradykinin and histamine.
(Runkel et al., 1972; Gfeller and Sandon, 1991; Isaacs, PGI 2 also inhibits platelet aggregation.
1996; Talcott, 2006; Koenigschof et al., 2015). Half of a NSAIDs bind the active site of COX, usually
given dose of naproxen is eliminated in the bile of dogs through competitive inhibition, although aspirin binds