Analgesic, Antiinflammatory, Antipyretic Drugs

Analgesic, Antiinflammatory, Antipyretic Drugs

Peter Lees

Scientific Literature

The published literature on nonsteroidal antiinflammatory drugs (NSAIDs) is voluminous in quantity but not always matched by quality; in amount, it is greater than any individual can read in a lifetime. For those wishing to rise to this challenge, the following chapters and reviews are recommended as a starting point: Vane, 1971; Warner et al., 1999; Flecknell and Waterman-Pearson, 2000; Lees et al., 2004a,b, 2015; Bergh and Budsberg, 2005; Robertson, 2005; Lascelles et al., 2005, 2007; Papich, 2007, 2008; Budsberg, 2009; Innes et al., 2010; Kukanich et al., 2012; Lees and Toutain, 2013). The reader is also referred to the USP monographs on individual drugs (Veterinary Medicine Expert Committee on Drug Information, 2004).

The Role of Eicosanoids in Inflammation and Mechanisms of Action of NSAIDs

Acute inflammation is characterized by the four cardinal signs of heat, redness, swelling, and pain, as first described by the Roman physician Celsus in the first century AD, to which Virchow added the fifth sign, loss of function, in the 19th century. Three of the cardinal signs involve the microcirculation, being caused by arteriolar dilatation and increased permeability of capillaries and postcapillary venules to protein, leading to formation of an inflammatory exudate rich in leukocytes. The infiltrate is first dominated by polymorphonuclear leukocytes and later by mononuclear cells, which transform to macrophages in the interstitial space. Leukocytes are the scavengers of the inflammatory process, engulfing microorganisms, particulate matter, and dead and dying cells, and releasing enzymes and chemicals, the mediators of inflammation. Inflammatory processes are driven by a wide range of mediators, synthesized de novo or released from cell storage sites, in a timed manner in both the early and resolution phases of acute inflammation and in chronic inflammation. Many mediators interact with other mediators by addition, antagonism, or synergism.

Arachidonic acid (AA), a 20-carbon ω-6 unsaturated fatty acid, plays a pivotal role in inflammation as the precursor of the eicosanoid group of mediators. AA is an esterified component of cell membrane phospholipid, released in tissue damage following the action of endogenous peptides, the lipocortins, which activate phospholipase A2. There are several isoforms of phospholipase A2 and it is the cytosolic 85-kDa isoform that normally supplies AA. AA serves as a substrate not only for prostaglandin (PG)H synthase, more commonly known as cyclooxygenase (COX), of which there are two isoforms COX-1 and COX-2, but also several lipoxygenases (LO), including 5-LO, 12-LO, and 15-LO. Each enzyme is a component of a cascade, in which the action of further enzymes leads to the formation of eicosanoids. They are described as autacoids, as they act locally at the site of synthesis. Moreover, they are short lived, so that continued effect depends on maintained synthesis and release. COX catalyses both the formation of PGG2 and then PGG2 conversion to PGH2 via a peroxidase function.

At an early stage of acute inflammation, several PGs (including PGE2, PGI2, and PGD2) are synthesized from AA, the product profile being determined by differing downstream enzymes. For example, cytosolic PGE synthase is mainly coupled with COX-1, whilst an inducible microsomal or membrane-associated perinuclear PGE synthase, regulated by cytokines and glucocorticoids, is coupled with COX-2 (Murakami et al., 1999).

PGs are cyclic five-carbon structures; the two COX isoforms generating PGs consist of a long narrow channel with a hairpin bend at the end. For COX-2 the substitution of valine for isoleucine creates a wider channel than for COX-1. Selective COX-2 inhibitors have a broader conformation, so that they enter the COX-1 channel less readily. A further difference is the kinetics of binding of NSAIDs to each isoform. COX-1 inhibition involves hydrogen bonding, is instantaneous and competitively reversible, except for aspirin. COX-2 inhibition may involve covalent binding, is time dependent, and slowly reversible.

Eicosanoid receptors are cell membrane spanning and G-protein coupled; several subdivisions have been classified, corresponding to each COX metabolite, for example DP for PGD2, EP for PGE2, FP for PGF, and IP for PGI2. The actions of PGE2 are mediated by a range of receptor subtypes (EP1, EP2, EP3, and EP4) activation of which leads to ongoing intracellular signaling pathways. The EP4 receptor is associated with inflammatory pain and has been implicated in rheumatoid and osteoarthritis (OA). Grapiprant, a selective EP4 receptor antagonist, is under development for use in dogs with OA (Rausch-Derra and Rhodes, 2015).

Following synthesis, PGs must exit the cell; ABC genes provide ABC transporters to consume ATP, facilitating transfer across cell membranes. For example, MRP4 has particular affinity for transporting PGE2, TxA2, and PGF (Warner and Mitchell, 2003).

Several examples of synergism between proinflammatory PGs and other inflammatory mediators may be cited. First, both histamine (Chapter 19) and bradykinin are primary inflammatory mediators, which stimulate nociceptors (peripheral nerve endings) to increase the discharge in afferent nerves, so that pain is sensed in spinal and brain centers. PGE2 synergizes with these primary mediators to increase both intensity and duration of the afferent discharge, a phenomenon termed hyperalgesia (Ferreira, 1983). In addition, when tissues are damaged, stimuli (e.g., touch) that are not normally painful, become painful, a phenomenon termed allodynia; PGs are again implicated (Nolan, 2001). It is by inhibiting PG synthesis that NSAIDs exert their analgesic actions.

Second, histamine and bradykinin increase endothelial intercellular gaps in capillary and small postcapillary venules, to increase loss of plasma into the interstitial space. This alteration to the Starling balance of forces causes exudation of plasma, accounting for one of the classical signs of acute inflammation, edema. PGs do not alter capillary permeability directly but, by dilating small arterioles, they enhance the edema induced by the primary mediators. Inhibition of synthesis of PGs by NSAIDs explains their antiedematous actions.

Third, there is synergy between proinflammatory mediators in the induction of COX-2 protein and in the supply of AA to enhance prostanoid production at inflammatory sites. Hamilton et al. (1999) showed that lipopolysaccharide (LPS)-induced COX-2 induction alone did not greatly increase prostanoid production, but it was markedly increased by bradykinin administration through an increase in the supply of the substrate AA.

COX-2 generates antiinflammatory as well as proinflammatory PGs; COX-2 is up-regulated not only in the early stage (2 hours) of acute inflammation but also in the resolution phase (around 48 hours). The early peak of COX-2 production is associated with the synthesis of proinflammatory PGE2 by polymorphonuclear leukocytes, while the later peak is associated with the synthesis of antiinflammatory PGs (Gilroy et al., 1998, 1999). These include 15deoxyΔ12−14PGJ2 (15dPGJ2) synthesized by mononuclear cells; 15dPGJ2 is a ligand for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) and some of its actions may result from activation of PPAR-γ (Kawahito et al., 2000). Inhibition of synthesis of 15dPGJ2 with COX-2 selective as well as with nonselective NSAIDs theoretically might lead to a more protracted resolution/ healing phase in acute inflammation (Konturek et al., 2005) although this has not been identified as a clinical problem.

As well as the peripheral/ local roles of PGs, they are involved in pain perception at the spinal level. Spinal nociceptive processing is facilitated by firing of neurons and enhancement of transmitter release from primary spinal sensory afferents. Furthermore, PGE2 is also an endogenous pyrogen, leading to upward resetting of the temperature regulating center in the anterior hypothalamus.

Proinflammatory PGs and leukotrienes (LTs) are synthesized from AA by the catalytic actions of COX and 5-LO, respectively. ω-3 fatty acids, present in high concentrations in fish oils, include eicosapentanoic acid (EPA) and docosahexanoic acid (DHA). EPA and DHA also serve as substrates for COX and 5-LO. They may thereby suppress the proinflammatory activities of AA both competitively and through the synthesis of products with less inflammatory or even antiinflammatory activity. 12-LO leads to 12-hydroperoxyarachidonic acid (12-HPETE) and 12-hydroxyarachidonic acid (12-HETE) formation, while 15-LO forms lipoxins A and B. The lipoxins possess antiinflammatory properties; together with 15dPGJ2 they may subserve roles in the resolution stage of acute inflammation. On the other hand, 5-LO generates the LT family of proinflammatory eicosanoids, such as LTB4 and the peptidoleukotrienes LTC4, LTD4, and LTE4. LTB4 is a potent proinflammatory chemoattractant, drawing first neutrophils and later mononuclear cells to inflammatory sites. Peptidoleukotrienes are potent bronchoconstrictors. LTs are mediators of local vascular and cellular changes at sites of nonimmune inflammation and also in immune-mediated inflammatory conditions. Possible roles of LTs in conditions such as reactive airway obstruction in the horse and skin allergies in the dog have been investigated, and the use of 5-LO inhibitors as well as inhibitors of the actions of released LTs as therapeutic agents in immune-based inflammatory diseases has been researched (Marr, 1998).

Isoforms of Cyclooxygenase: Characteristics, Locations, and Roles

Cyclooxygenase-1 (COX-1)

COX-1 is a membrane-bound enzyme present in the endoplasmic reticulum (Table 20.1). It first cyclizes AA to form PGG2 and then adds a 15-hydroperoxy group to convert PGG2 to PGH2. COX-1 is expressed constitutively in most tissues. It is involved in “housekeeping” functions, including blood clotting, regulation of vascular homeostasis, renoprotection, gastroprotection, and coordination of the actions of circulating hormones.

Table 20.1 Characteristics, actions, and roles of COX-1 and its inhibition

A membrane-bound hemo- and glycoprotein of molecular weight 71 kDa, present in the endoplasmic reticulum
Encoded by a 22-kb gene
Constitutively expressed by cells in a wide range of tissues; involved in “housekeeping” functions
Enzyme concentrations are relatively stable, although small (two- to fourfold) increases occur in response to stimulation by hormones and growth factors
Responsible for generation of TxA2 and PGs, e.g., PGE2 and PGI2 with local actions, such as gastroprotection, renoprotection, and hemostasis
Inhibited by classical NSAIDs which generally are nonselective for COX-1 and COX-2
NSAIDs, which may show some selectivity for inhibition of COX-1 relative to COX-2, include aspirin and ketoprofen.
Aspirin irreversibly inhibits COX-1 by covalent acetylation of amino acid Ser 530. Other NSAIDs inhibit COX-1 reversibly by excluding arachidonic acid from the upper portion of a long, hydrophobic channel

COX, cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin.

Cyclooxygenase-2 (COX-2)

COX-2 is both an inducible and constitutive isoform (Table 20.2) (Wooten et al., 2008). COX-2 synthesis is stimulated by proinflammatory cytokines, growth factors, lipopolysaccharide (LPS), and mitogens. The cloning, expression, and selective inhibition of canine COX-1 and COX-2 have been reported (Gierse et al., 2002). While most data support COX-2 as the isoform which generates pro- and antiinflammatory PGs at sites of inflammation, some data indicate a role for COX-1 as well (Smith et al., 1998; Bertolini et al., 2001).

Table 20.2 Characteristics, actions, and roles of COX-2 and its inhibition

Molecular weight of 70 kD and having 60% homology with COX-1 at the amino acid level
Has similar active sites to COX-1 for binding AA and NSAIDs, although the active site of COX-2 is larger and more flexible than that of COX-1 and can accept a wider range of structures as substrates
Encoded by an 8.3-kb gene
One of a family of primary response genes induced during inflammation and cell growth
Unlike COX-1 possesses a TATA box and binding sites for transcription factors, e.g., NFκB and a cyclic AMP response binding element in the promoter region of the immediate-early gene
A better competitor than COX-1 for AA released within the cell
Expression increased on exposure to lipopolysaccharide, cytokines (e.g., IL-1, TNF-α) immune and inflammatory stimuli
Present constitutively in monocytes, macrophages, pyloric and duodenal mucosa, endothelial cells, brain, dorsal horn cells of spinal cord, kidney, ovary, uterus, and ciliary body in the eye
Produces proinflammatory PGs (e.g., PGE2) in the early stages of the acute inflammatory response and antiinflammatory PGs (e.g., 15dPGJ2) in the resolution phase
Down-regulated at the mRNA level by corticosteroids.
Exerts significant roles in certain cancers, Alzheimer’s disease, and arthritides, and activation inhibits apoptosis (NSAIDs induce apoptosis)
Aspirin preferentially inhibits COX-1 (acetylating Ser 530), although higher concentrations also acetylate irreversibly Ser 516 on COX-2. Other NSAIDs compete reversibly with AA, the substrate for COX-1 and COX-2 for the active sites on the enzymes
Specific and selective inhibitors of COX-2, the COXIBs, are antiinflammatory and analgesic and have better gastrointestinal tolerance than many nonselective COX inhibitors

AA, arachidonic acid; COX, cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin.

History of NSAIDs

The antecedents of the modern range of NSAIDs were extracts of various plants, in therapeutic use for more than 3,500 years, and comprising particularly the leaves and bark of the willow tree. These contain salicyl alcohol in free form or as glycosides such as salicin. The antiinflammatory properties of willow extracts were described by Dioscorides in his pharmacopoeia in the first century AD, as follows: “the leaves being beaten small and dranke with a little pepper and wine doe help such as are troubled with the Iliaca Passio (colic) … the concoction of ye leaves and barke is an excellent fomentation for ye gout.” The Rev. Edward Stone described, in 1795, the antipyretic properties (cure of agues) of the willow noting, “as this tree delights in a moist or wet soil, where agues (fever) chiefly abounds the general maxim that many natural remedies carry their cures along with them or that remedies lie not far from their causes was so very apposite to this particular case that I could not help applying it.” The “like cures like” concept was fashionable at that time, and persists in the nonscience of homeopathy to this day.

Discovery of salicyl alcohol/ salicylic acid as the active principles of plant extracts led to the use of sodium salicylate as the first synthetic NSAID in 1875 and then to the introduction of the acetyl ester of salicylic acid (aspirin) in 1898. By the sixth decade of the 20th century, aspirin, cinchophen, phenylbutazone, dipyrone, and isopyrin were, for several years, the commonly used NSAIDs in veterinary therapy. In the 1970s, flunixin was introduced and subsequently many novel NSAIDs have received marketing authorizations. Over the last 20 years in particular, there have been intensive searches for novel agents within the NSAID class, stimulated by several factors.

First has been the recognition that animals feel and suffer pain in a manner similar to the human animal. The welfare benefit of controlling animal pain is widely recognized. Second, it has been recognized that available drugs of the NSAID class, while commonly very efficacious, do not consistently in all animals or in all circumstances provide adequate levels of analgesia, especially when pain is severe. Third, the need to improve safety margins, notably in relation to gastrointestinal (GI) tolerance of NSAIDs, but also to ensure renal safety and to avoid uncontrolled hemorrhage, has been acknowledged. Most NSAIDs are clinically safe when used at recommended dose rates. However, there are several qualifications: there are equine examples (see Sections Additional actions of NSAIDs: gastrointestinal toxicity; renotoxicity; and hepatotoxicity) of narrow margins between clinically recommended NSAID doses and doses causing significant toxicity; side effects may be related to age and physiological/ pathological status (e.g., conditions and circumstances involving hypotension and hypovolemia predispose towards renotoxicity); NSAID toxicity may be idiosyncratic, occurring rarely but unpredictably, even with manufacturers’ recommended dose rates. Therefore, safety concerns on older drugs have driven the search for novel agents.

Classification of NSAIDs, Chemical Structures, and Physicochemical Properties

Classifications based on chemical structure are of limited value because, despite minor differences between subgroups, all older NSAIDs have similar pharmacological actions (analgesic, antiinflammatory, and antipyretic), toxicity profiles, and clinical uses. Moreover, physicochemical properties are generally similar; almost all are weak organic acids (pKa in the order of 3.5–6.0) and of moderate to high lipid solubility (Veterinary Medicine Expert Committee on Drug Information, 2004).

The older (classical) NSAIDs are divided on the basis of chemical structure into two main groups: carboxylic acids and enolic acids, further divided into subgroups on the basis of chemical structure (Table 20.3, Figure 20.1). NSAIDs of the 2-arylpropionate group contain a single center of asymmetry; they are therefore chiral compounds. They are produced commercially as racemic (50 : 50) mixtures of the two optical enantiomers (R[−] and S[+]) and thus comprise a mixture of two drugs with differing pharmacokinetic and pharmacodynamic profiles.

Table 20.3 Chemical classification of classical NSAIDs

Carboxylic acids (R-COOH) Enolic acids (R-COH)
Salicylates Oxicams
Sodium salicylateb Meloxicama
Acetylsalicylic acida Piroxicam
Indoleacetic acids Tenoxicam
Etodolaca Pyrazolones
Indolines Phenylbutazonea
Indomethacin Oxyphenbutazonec
Thiopheneacetic acids Isopyrin (ramifenazone)a
Diclofenac Dipyronea
2-Arylpropionic acids            
Anthranilic acids            
Meclofenamic acida            
Tolfenamic acida            

a Drugs currently or previously licensed for veterinary use in some countries.

b Also a metabolite of acetylsalicylic acid.

c Also an active metabolite of phenylbutazone.

Diagram shows chemical compound structure of aspirin, arachidonic acid, ketoprofen, carprofen, meloxicam, et cetera.

Figure 20.1 Structures of arachidonic acid and classical NSAIDs (aspirin, ketoprofen, carprofen, tolfenamic acid, and meloxicam) and COXIBs [firocoxib (methylsulfone), mavacoxib / cimicoxib (sulphonamides) and robenacoxib (carboxylic acid)]. * site of asymmetric carbon atom.

Novel SAID Classes

COX-2 inhibitors:

The COXIBs are preferential or selective inhibitors of COX-2. They have differing structures to classical NSAIDs (Figure 20.1). Most are sulphones or sulphonamides, although robenacoxib is exceptional, being a carboxylic acid. The sulphones and sulphonamides are lipophilic compounds. Their relatively bulky structure limits COX-1 inhibition by steric hindrance. They have provided a significant advance in pain therapy (Wilson et al., 2004). The introduction of firocoxib into canine medicine for the therapy of canine OA comprised the first COX-2 selective drug for veterinary use (McCann et al., 2004), and others, including cimicoxib, deracoxib, mavacoxib, parecoxib, and robenacoxib, have followed.


COX-inhibiting nitric oxide donors (CINODs) are nitrosoesters of the older nonselective COX inhibitors (e.g., aspirin, phenylbutazone). The ester linkage is hydrolyzed in vivo to yield parent NSAID and the vasodilator nitric oxide (NO). The latter may enhance potency and increase gastric tolerance (Wallace et al., 2004). No drug of this class has been introduced into veterinary therapeutics.

Dual COX/5-LO inhibitors:

The dual inhibitor tepoxalin was introduced into canine medicine (Argentieri et al., 1994) but drugs of this class have found only limited use in veterinary medicine.

Pharmacology of NSAIDs

NSAID Pharmacokinetics


As lipid-soluble weak organic acids, classical NSAIDs are generally well absorbed when administered orally (Table 20.4), although rate and extent of absorption vary with species, gastric pH, dosing in relation to feeding, and gastrointestinal motility. In monogastric species, absorption from the stomach is favored by the Henderson–Hasselbalch ion trapping mechanism, which maintains a diffusion gradient for undissociated acid molecules between acidic gastric juice and plasma of pH 7.4. In ruminants, initial absorption from the four-compartment stomach and subsequent intestinal absorption creates the basis for a biphasic absorption pattern. In young ruminants, operation of the esophageal groove reflex is another mechanism accounting for double peaks in plasma concentration (Marriner and Bogan, 1979). Despite dilution in a large volume of rumen liquor (approximately 120 liters in an adult cow), bioavailability of phenylbutazone and meclofenamate was shown to be 50–60% in cattle (Lees et al., 1988a; Marriner and Bogan, 1979).

Table 20.4 General pharmacokinetic properties of NSAIDs

Generally good bioavailability in monogastric species after oral dosing. Absorption may be (a) delayed by binding to digesta (e.g., in horses and ruminants) (b) enhanced or reduced in the presence of food
Good bioavailability after parenteral (IM, SC) dosing
Penetrate blood–brain barrier to act centrally
High degree of plasma protein binding of all drugs (except salicylate) in all species limits passage from plasma into interstitial and transcellular fluids but facilitates passage into inflammatory exudate
Glomerular ultrafiltration and the renal excretion of parent drug markedly limited by high degree of plasma protein binding
Low volume of central compartment and low volume of distribution (with some exceptions, e.g., most COXIBs)
Elimination predominantly by metabolism in liver, usually to inactive compounds, but some metabolites are active, e.g.,  Phenylbutazone → oxyphenbutazone  Aspirin → salicylate
For most drugs marked species (and possibly breed) differences in clearance and elimination half-life
Reduced clearance, increased half-life in neonates
Biliary secretion and enterohepatic recycling for some drugs

COXIB, cyclooxygenase inhibitor.

There are exceptions to the high bioavailability of NSAIDs after oral dosing. Bioavailability in horses was <5% for an oil-based formulation of RS-ketoprofen. However, when the pure drug substance was administered, bioavailability was of the order of 50% (Landoni and Lees, 1995). Another factor affecting absorption rate, of significance in the horse, is binding to hay (shown in vitro) and to digesta (demonstrated in vivo) (Lees et al., 1988b). Binding delayed the absorption of phenylbutazone and flunixin, accounting for double peaks in plasma concentration–time curves (Maitho et al., 1986; Welsh et al., 1992). In monogastric species, administration of NSAIDs with food is a common practice, as it may lessen irritant effects on the GI. As in horses, this practice is likely to delay absorption but to reduce absorption only moderately or not at all. However, the bioavailability of mavacoxib was higher in fed (87%) than in fasted (46%) dogs, while the converse was true for robenacoxib in both the dog (62 and 84%, respectively) and cat (10 and 49%, respectively) (Cox et al., 2010; Jung et al., 2009; King et al., 2013). As well as feed, other factors, including product formulation, may influence the rate and/or extent of absorption of NSAIDs. For example, aspirin is available in plain, water-soluble, film-coated, buffered, enteric-coated, and time-release formulations, with differing disintegration and dissolution rates.


Most NSAIDs are highly bound to plasma protein (95–99% or greater). This limits passage from plasma into interstitial fluid. The volumes of the central compartment and distribution are generally low and values of 0.1–0.3 l/kg or less are common. There are exceptions, however, and moderate to high volumes of distribution have been reported for flunixin in cattle (but not in other species); for tolfenamic acid in the dog, calf, and pig; and for all sulphones and sulphonamide COXIBs (but not for the carboxylic acid derivative robenacoxib) in the dog. Contributing to these high distribution volumes for COXIBs is enterohepatic recirculation or a high level of extravascular accumulation/ tissue binding.

A potential therapeutic advantage of the high degree of plasma protein binding is accumulation of NSAIDs in inflammatory exudate. Since exudate is rich in albumin, which has leaked from the circulation, the binding of NSAIDs to albumin accounts for ready penetration into and persistence at sites of acute inflammation (Table 20.5). Exudate concentrations of NSAIDs often exceed those in plasma when drug body clearance is high and terminal half-life is short. Accumulation in exudate is a likely explanation for: (i) the maintained effectiveness of NSAIDs when plasma concentrations have decreased to low levels and (ii) why those NSAIDs with short elimination half-lives, for example flunixin, ketoprofen, vedaprofen, tolfenamic acid, and robenacoxib, may be effective with once-daily dosing. This longer duration of effect than predicted from plasma concentration–time profile is associated with the negative hysteresis described in in vivo studies, which indicate that maximal inhibition of PGE2 synthesis in exudate occurs some time after peak drug concentrations in plasma (Giraudel et al., 2005b; Pelligand et al., 2012, 2014). The latter group reported elimination half-lives from feline exudate for S-ketoprofen and robenacoxib of 26 and 41 hours, respectively; corresponding values for blood were 1.62 and 1.13 hours after subcutaneous administration. Exudate PGE2 concentration was reduced for 24–36 hours. In clinical OA dogs, the synovial fluid concentration of robenacoxib exceeded the IC50 for COX-2 for 16 hours; the corresponding time for healthy beagles was 10 hours (Silber et al., 2010).

Table 20.5 Examples of penetration into acute inflammatory exudate and transudate relative to plasma

                        AUC (μg·h/ml)
Administered drug Species Dose (mg/kg) Plasma Exudate Transudate
RS-carprofenb 1 Horse 4.0  558 (R)     451 (R)    336 (R)
                         138 (S)    133 (S)     93 (S)
Flunixina 2 Calf 2.2   11.8    27.6    7.0
Flunixina 3 Horse 1.1   19.3    36.0   12.1
S-ketoprofena 4 Horse 1.1    2.7    32.6    3.4
S-ketoprofena 5 Calf 1.5   13.2    26.1   20.9
Phenylbutazonea 6 Horse 4.4  156  128  49
Phenylbutazonea 7 Donkey 4.4   19.2     8.0    5.0
Phenylbutazoneb8 Calf 4.4 3604 1117 766

a Short plasma elimination half-life;

b longer half-life.

Data from 1Armstrong et al. (1999a); 2Landoni et al. (1995c); 4Landoni and Lees (1996); 5Landoni and Lees (1995); 6Lees et al. (1986); 7Cheng et al. (1996); 8Arifah et al. (2002).

For the 2-arylpropionate NSAIDs, enantioselectivity of distribution into exudate (Table 20.5) and synovial fluid (Armstrong et al., 1999a) has been demonstrated. This impinges on efficacy, as the two enantiomers exhibit pharmacodynamic differences as well (see Section NSAID pharmacodynamics: Inhibition of COX and 5-LO).

For those COXIBs based on sulphonamide or sulphone structures, the molecules are nonionized at physiological pH and volumes of distribution are high, whereas robenacoxib, a carboxylic acid, resembles most nonselective NSAIDs in having a low distribution volume.

A possible consequence of NSAID plasma protein binding is competition with other protein-bound drugs; theoretically this can lead to acute toxicity of either drug as the free concentration is increased. Nephrotic animals have reduced plasma protein concentrations and some authors have suggested that this may predispose to NSAID toxicity. However, in both of these circumstances, this will rarely be clinically significant, as the free concentration quickly falls, being subject to redistribution, metabolism, and excretion (Toutain and Bousquet-Melou, 2002).

The penetration of NSAIDs into milk in the absence of mammary gland infection is poor, milk concentrations being of the order of 1% or less of plasma total concentration. This results from the high degree of binding to plasma protein. Distribution into milk is also limited by the Henderson–Hasselbalch mechanism, as milk pH is less than that of plasma. In mastitis, however, penetration is likely to be increased from these low levels.

Excretion and Metabolism (Elimination)

As classical NSAIDs are weak organic acids, elimination in urine might be expected to vary with urine pH. In principle, ion trapping of the poorly lipid-soluble ionized moiety in alkaline urine will favor excretion in herbivores (horses and ruminants) but not in omnivores and carnivores (dogs and cats), as their urine is generally acidic. However, of over-riding importance for urinary excretion in all species is the high degree of plasma protein binding, which limits passage into glomerular ultrafiltrate to a small proportion of the total drug concentration in plasma. Hence, for most NSAIDs only small fractions of the administered dose are excreted in unchanged form in urine, irrespective of species and urine pH. This is illustrated by phenylbutazone excretion in the alkaline urine of horses; as a percentage of administered dose, the 24-hour excretion was 1.9 (Lees et al., 1987b). There is evidence for biliary secretion of some NSAIDs (e.g., carprofen) creating the basis for possible enterohepatic recirculation (Priymenko et al., 1993). Mavacoxib is also secreted in bile and its prolonged elimination half-life is due, in part, to repeated reabsorption of secreted drug but also to its high distribution volume (Lees et al., 2015).

Most NSAIDs are eliminated primarily by hepatic metabolism to less active (or inactive) phase 1 metabolites, which undergo conjugation phase 2 reactions to more polar, readily excreted conjugates. However, some drugs, such as aspirin and phenylbutazone, are converted to active metabolites, salicylate and oxyphenbutazone, respectively (Lees et al., 1987a,b). The deacetylation of aspirin is, in part, a spontaneous reaction, so that aspirin has a half-life of only several minutes in plasma. Therefore, salicylate accounts for most of the analgesic and antiinflammatory properties of administered aspirin, although aspirin itself accounts for the platelet-based antithrombotic actions. This is because aspirin blocks platelet COX covalently and irreversibly and therefore for the lifespan of the platelet. This permanent inhibition of platelet COX occurs after exposure for only a limited period, so that the short half-life of aspirin (approximately 9 minutes) in the horse does not limit platelet COX-1 inhibition for several days (Lees et al., 1987a).

Examples of elimination half-life are presented in Table 20.6. Interpretation of these values must take account of the fact that half-life is a hybrid variable, controlled by body clearance and volume of distribution.

Table 20.6 Terminal half-life of NSAIDs (intravenous administration unless stated)

Species Salicylate Flunixin Meloxicam Carprofen S(+) R(−) Ketoprofen S(+)R(−) Naproxen Tolfenamic Acid
Horse 1.0–3.0 1.6–2.1 3 16, 21 1.0, 0.7 5 7.3
Cow/calf 0.5, 3.7 (PO) 8 13 37, 50 0.4, 0.4 11.3
Pig 5.9 4 5 3.1
Dog 8.6 3.7 12–36 7, 8 3.5c 35–74b 5.3
Cat 22–45a 37 15, 20 1.5, 0.6 10.8
Monkey 1.9
Man 3.0 (PO) 20–50 12c 14

a Dose-dependent pharmacokinetics.

b Breed-dependent pharmacokinetics (lower value refers to beagles, higher value to mongrels).

c Values quoted in the literature for total drug (combined R and S enantiomers) a concept that is flawed. For the COXIBs see Table 20.12.

Species differences in some pharmacokinetic variables are the rule rather than the exception for NSAIDs. For example, while plasma protein binding is almost invariably very high and volumes of distribution are low for classical NSAIDs in most species, clearance and terminal half-life vary markedly. The example of phenylbutazone is presented in Table 20.7. Aspirin, like phenylbutazone, provides a useful example of the impact of elimination on dosing intervals. The terminal half-life of its metabolite salicylate ranges from 32 minutes in cattle to 22–45 hours in the cat, in which species elimination is zero order (dose-dependent pharmacokinetics).

Table 20.7 Species differences in phenylbutazone pharmacokinetics

            Elimination Clearance
Species half-life (h) (ml/h/kg)




The pharmacokinetics of the 2-arylpropionate subgroup of NSAIDs (carprofen, ketoprofen, and vedaprofen) is influenced by the possession of a single chiral center. There are therefore two mirror-image enantiomeric forms, R and S. The licensed products are the racemic (50 : 50) mixtures. Etodolac, though not a 2-arylpropionate, also possesses a single chiral center. The importance of NSAID chirality derives from the fact that the body is a chiral environment, whose cell membranes, macromolecules, and enzymes are based on D-monosaccharides and L-amino acids. Therefore, while NSAID enantiomers have virtually identical physicochemical properties, they do not have the same pharmacological properties in the body’s chiral environment, as manifested by both pharmacokinetic and pharmacodynamic differences. Pharmacokinetic data based on “the total drug” concept must be viewed with alarm; such data comprises “highly sophisticated scientific nonsense” (Ariens, 1985) because racemic mixtures are simply combinations, in equal proportions, of two distinct drugs. Pharmacokinetic differences are reflected in clearance, elimination half-life, and plasma area under curve (AUC) ratios for the two enantiomers. As illustrated by carprofen, AUC ratios vary between species and may be as high as 4 : 1, despite the 1 : 1 ratio in the administered products (Tables 20.5 and 20.8).

Table 20.8 Species variation in stereoselective pharmacokinetics of carprofen enantiomersa

                        AUC (% of total)
            Dose of Rac-carprofen Administration route                        
Species (mg/kg) (and dosing duration) R (−) S (+)
Dog (beagle)1 4.0 Oral 64 36
Dog (various breeds)2 2.0 Oral (day 1) 52 48
            Oral (day 7) 52 48
            Oral (day 28) 57 43
Cat3 0.7 Intravenous 69 31
            0.7 Subcutaneous 67 33
            4.0 Intravenous 70 30
            4.0 Subcutaneous 72 28
Calf4 0.7 Intravenous 58 42
Horse5,6 0.7 Intravenous 80–84 16–20
            4.0 Intravenous 80 20
Sheep7 4.0 Intravenous 74 26

a Single dose unless stated.

1 McKellar et al., 1994.

2 Lipscomb et al., 2002.

3 Taylor et al., 1996.

4 Delatour et al., 1996.

5 Lees et al., 2002.

6 Armstrong et al., 1999a.

7 Cheng et al., 2003.

Differences in pharmacokinetics for each enantiomer of chiral NSAIDs may arise in two ways. First, there are enantiomer differences in elimination, arising from differing rates of hepatic metabolism (Soraci et al., 1995). Second, for some drugs chiral inversion occurs in vivo. This, almost invariably, is unidirectional, comprising R to S inversion. Species (and breed) differences in the extent of chiral inversion of ketoprofen have been investigated (Table 20.9). There is also inevitable interanimal variation in the pharmacokinetics of NSAIDs. Table 20.10 presents data for firocoxib in beagles.

Table 20.9 Species differences in extent of chiral inversion of R(−)- to S(+)-ketoprofen

Species (% of administered dose)
Sheep (female, Dorset Cross)
Sheep (male, Corriedale)

Table 20.10 Interanimal variation in firocoxib pharmacokinetics in the beagle doga

Parameter Mean Range
Cmax (μg/ml)
Tmax (h)
AUC (μg/ml·h)
T1/2el (h)b

a Eight young beagles, both sexes: 5 mg/kg single dose administered orally (McCann et al., 2004).

b T1/2 values reported for other species are: 9–12 h (cat) and 30–40 h (horse).

As well as interanimal and interbreed differences, a report on celecoxib in a colony of 245 beagle dogs revealed a within-breed difference; two subpopulations were identified, an extensive metabolizer (EM) phenotype for which mean half-life was 1.72 hours and clearance was 18.2 ml/kg/min, and a poor metabolizer (PM) phenotype for which corresponding values were 5.18 h and 7.15 ml/kg/min (Paulson et al., 1999). This example points to the possibility of significant genetic differences in clearance and terminal half-life of other NSAIDs. In fact, similar within-breed (beagle) pharmacokinetic differences (EM and PM phenotypes) have been described for cimicoxib (Jeunesse et al., 2013). Respective clearances were 0.31 and 0.11 l/h/kg. In a lameness model, duration of action was greater in the PM dogs. These authors also administered cimicoxib to dogs of four breeds; half-lives were of the same order of magnitude as those of the EM beagles.

In addition to species, inter- and intrabreed, and interanimal differences in NSAID pharmacokinetics, there are inevitable intraanimal differences, arising from pathological or physiological state. Lascelles et al. (1998) reported, in dogs undergoing anesthesia, greater values of Cmax (20.6 versus 11.0 μg/ml) and AUC (175 versus 115 μg/ml·h) when carprofen was administered postoperatively compared to preoperatively. In adult cows with an E. coli endotoxin-induced mastitis, values of AUC and clearance were 507 mg/l·h and 1.4 ml/kg/h for carprofen (Lohuis et al., 1991) whilst values for healthy cows were 294 mg/l·h and 2.4 ml/kg/h. Age may affect the pharmacokinetics of NSAIDs. Clearance is likely to be slower and half-life longer in neonates, as established for phenylbutazone in goats (Eltom et al., 1993) and as suggested for carprofen in young calves (Lees et al., 1996; Delatour et al., 1996) and for phenylbutazone in older horses (Lees et al., 1985). The effect of an endurance exercise on phenylbutazone pharmacokinetics in the horse was investigated by Authie et al. (2010) in relation to medication control; hepatic clearance was decreased, as also was volume of distribution, so that terminal half-life was not changed.

In the dog the clearance of COXIBs differs between the extremes of robenacoxib and mavacoxib (Table 20.11); 13.5 ml/min/kg (robenacoxib) and 0.045 ml/min/kg (mavacoxib) and respective half-lives were 0.63 hours and 17 days in laboratory (beagle or mongrel) dogs. In the cat the elimination half-life of robenacoxib was 0.78 to 1.49 hours and was independent of administration route – intravenous, oral, or subcutaneous (King et al., 2013; Pelligand et al., 2012). Mavacoxib biotransformation and renal excretion in the dog are very limited; elimination is predominantly by biliary secretion and excretion in feces, and enterohepatic recirculation contributes to the slow clearance and long terminal half-life. Lees et al. (2015) calculated that the maximum amount excreted daily in bile was less than 10% of the monthly dose. Based on dose normalized plasma AUC, the pharmacokinetics of mavacoxib administered orally did not differ between mongrel and beagle dogs and was proportional to dose over the range 2–25 mg/kg (Cox et al., 2010).

Table 20.11 Comparative pharmacokinetics of five COXIBs in Beagle or mongrel dogsa

Variable (units) Route Mava coxib Robenacoxib Firocoxib Deracoxib Cimicoxibc Cimicoxibd
Cl (ml/min/kg)b IV 0.045 13.5 7.7 5 5.2 1.8
t1/2 (h or days) IV 17 days 0.63 h 5.9 h 3 h 2.72 h 5.63 h
Vdss (l/kg) IV 1.64 0.24 2.9 1.5 1.12 0.89
Plasma protein binding (%) IV >98 >98 >90
Tmax (h) (fed dogs) Oral 17.4 0.25 2.0
Tmax (h) (fasted dogs) Oral 67.4 0.5 1.0
F (%) (fed dogs) Oral 87 62 >90
F % (fasted dogs) Oral 46 84 101

a Data from Cox et al. (2010); McCann et al. (2004); Jung et al. (2009); Jeunesse et al. (2013); Deracoxib commercial literature.

b Clearance values can be compared with the value of 5.8 ml/kg/min defined by Toutain and Bousquet-Melou (2004) as a “low” value for dogs weighing 10 to 20 kg. This value emphasizes the particularly low clearance of mavacoxib.

c Extensive metabolizes.

d Poor metabolizes.

Cl, body clearance; t1/2 elimination half-life; Vdss, volume of distribution at steady state; Tmax, time of maximum concentration; F, bioavailability.

However, in population pharmacokinetic studies, in mainly elderly large breed dogs with OA, the mean elimination half-life of mavacoxib was longer (44 days) than the half-life of 17 days in laboratory dogs and in approximately 5% of OA dogs T1/2 exceeded 80 days. This led to reduction in the dose predicted from laboratory dogs of 4 mg/kg to 2 mg/kg, with a dosing interval of 14 days between first and second doses and 28 days between subsequent doses and with a duration of therapy limited to 6 months (Cox et al., 2011). These authors reported body weight as the primary factor predicting clearance and distribution volume (both scaled by bioavailability) and with smaller effects of age and breed. In a clinical population of OA dogs, it was shown that apparent clearance and volume of distribution of robenacoxib were likewise proportional to body weight (Fink et al., 2013). Clearly, there is a need to conduct population pharmacokinetic studies in clinical subjects on other NSAIDs.

Parecoxib is an inactive prodrug, with a short half-life (0.42 hours) after intramuscular injection in the cat; it is converted in vivo to the active metabolite valdecoxib (T1/2 = 8.52 hours; Kim et al., 2014).

Baert and De Backer (2003) provided valuable comparative pharmacokinetic data for sodium salicylate, flunixin, and meloxicam in five bird species, chicken, ostrich, duck, turkey and pigeon; species differences were marked.

Drug Residues

Regulatory authorities require that meat and milk withholding periods be established for NSAIDs licensed for use in food-producing species, including the horse. These are set on the basis of each drug’s pharmacokinetic, metabolism, tissue depletion, and toxicological profiles, together with an appropriate safety margin. The relevant considerations for phenylbutazone have been reviewed (Lees and Toutain, 2013). This area is reviewed in Chapter 61 of this text.

NSAID Pharmacodynamics

Inhibition of COX and 5-LO

In addition to pharmacokinetic differences, a second basis for the variation in clinical response to NSAIDs between species, breeds, and individual animals is differences in their pharmacodynamics. This has been studied at several body levels: molecular, cellular, tissue, and whole animal, and can be considered in terms of the action–effect–response relationship (Table 20.12). The principal action is inhibition of COX, the enzyme with a pivotal position in the AA cascade; NSAIDs occupy the hydrophobic channel of COX, preventing AA access to its active site. This leads to the effect of inhibition of synthesis of proinflammatory mediators, including PGE2 and PGI2. The action and effect have been demonstrated with clinically achieved concentrations of many NSAIDs in several species (Lees and Higgins, 1985; Landoni and Lees, 1995, 1996; Landoni et al., 1995a,b,c; Cheng et al., 2003; Jones et al., 2002). The responses are the analgesic, antipyretic, antiinflammatory, antithrombotic, and antiendotoxemic properties of NSAIDs (Lees et al., 1986; Welsh and Nolan, 1994; Welsh et al., 1997; Nolan, 2001; Giraudel et al., 2005b). Current evidence suggests that a high level (80% or higher) of inhibition of PGs may be required to achieve good clinical responses.

Table 20.12 Principal action–effect–response relationships of NSAIDs

Actions Inhibition of COX-1, COX-2, and, for some drugs, 5-LO
Effects COX inhibition: reduced synthesis of eicosanoids with : proaggregatory and vasoconstrictor properties (TxA2); antiaggregatory and vasodilator properties (PGI2); proinflammatory properties (PGE2, PGD2, PGI2); and antiinflammatory properties (15deoxyΔ12−14PGJ2)
5-LO inhibition: for dual inhibiting NSAIDs only, decreased synthesis of proinflammatory leukotrienes (LTB4, LTC4, LTD4, LTE4)
Responses Reduction of raised body temperature (antipyretic), suppression of pain (analgesic/antihyperalgesic), decreased swelling (antiinflammatory) and possibly reduced rate of recovery in the resolution phase of acute inflammation – not clinically significant as far as known

COX, cyclooxygenase; LO, lipoxygenases; PG, prostaglandin.

Vane (1971) discovered that the principal mechanism of action of NSAIDs was inhibition of COX. A further advance occurred with the discovery of two COX isoforms, COX-1 and COX-2 (Kujubu et al., 1991; Xie et al., 1991). It was immediately recognized that most classical NSAIDs inhibit both isoforms, COX-1 inhibition producing toxic effects and COX-2 inhibition providing therapeutic effects. COX-1 was classified as a constitutive enzyme with physiological/ housekeeping functions, including gastro- and renoprotection and blood clotting leading to hemostasis. COX-2 was initially regarded solely as an inducible enzyme, up-regulated at sites of inflammation and responsible for producing proinflammatory mediators. Since 1991, much effort has been directed to identifying the following: which tissues express the two isoforms constitutively; the physiological and pathological roles of each isoform; the role of COX-2 induction at sites of inflammation and centrally; and the nature, incidence, and severity of side effects of drugs that inhibit one or both isoforms.

The overall roles of COX isoforms and the actions of NSAIDs, as perceived in 1991, have been modified as follows:

  1. Warner and Mitchell (2003) have concluded that there are only two genes for COX enzymes, COX-1 and COX-2 and not a third, COX-3, as earlier postulated.
  2. It is now recognized that COX-2 is a constitutive enzyme, present in stomach, brain, spinal cord, kidney, ovary, uterus, and ciliary body. Therefore, it has been postulated that complete inhibition of COX-2, especially over long periods, might be associated with such side effects as abortion, fetal abnormalities, delayed bone healing, delayed healing of soft tissue (including delayed ulcer healing), renotoxicity, and “adverse cardiovascular events.” However, the now extensive clinical use over prolonged periods of COXIBs has been associated with a generally good safety profile. Nevertheless, COXIBs are not free of adverse effects on the GI and there remains controversy over the cardiovascular events associated with their clinical use, especially in human medicine when administered over prolonged periods. COX-2 is both constitutive and inducible in endothelial cells and its selective inhibition might disturb the endothelial PGI2 (an antiaggregatory and vasodilator PG synthesized via COX-1 and COX-2) platelet TxA2 (a proaggregatory and vasoconstrictor eicosanoid synthesized by COX-1) balance in the direction of platelet aggregation and vasoconstriction. The cardiovascular events in humans, which have been the subject of much public discussion, might reflect this imbalance. However, some reports have suggested an increased cardiovascular risk in humans receiving long-term therapy with nonselective as well as COX-2 selective drugs. Epidemiological studies in animals reviewing such risks have not been reported.
  3. Some reports indicate that COX-1 may contribute to the synthesis of proinflammatory PGs. Therefore, as well as COX-2 inhibition, inhibition of COX-1, as provided by the older nonselective NSAIDs, might be required for optimal efficacy. However, this concept is controversial and most experimental and clinical data suggest that selective COX-2 inhibitors are as efficacious as nonselective NSAIDs.
  4. The introduction of a novel class of NSAIDs, the dual inhibitors, including tepoxalin, which inhibit two enzymes that use AA as a substrate, COX and 5-LO, has failed to make a major impact in veterinary medicine.

Efficacy, Potency, and Sensitivity of Inhibitory Actions of NSAIDs on COX Isoforms

As discussed in Chapter 4, the pharmacodynamic properties of any drug that define and quantify its action on a given tissue, organ, or enzyme are efficacy, potency, and sensitivity. Efficacy (Imax/Emax) is the maximal response a drug is capable of producing. It is important to the clinician because it defines, for example for a NSAID, the level of pain relief that the drug can provide. Potency is the drug concentration or drug dose producing a given level of response. It is usually determined as the concentration or dose producing 50% of maximal response (EC50 or ED50) or, for drugs such as NSAIDs acting to inhibit an enzyme, potency is usually expressed as IC50, although IC80 can be more useful. Potency is of less relevance than efficacy to the clinician, but it is critical to pharmaceutical companies when selecting a recommended dose rate for clinical use. NSAID concentration–response data are described by the sigmoidal Emax (Hill) relationship (Chapter 4) and the steepness of this relationship (N) determines sensitivity. For NSAIDs, slope may be shallow (less than 1) or steep (10 or greater) and in the latter circumstance the concentration–effect relationship becomes almost quantal (all-or-none).

In vitro assays have been used to determine Imax, IC50, IC80, IC95, etc., and N of NSAIDs for each COX isoform. Depending on both the relative positions and slopes of the two curves, it is possible to determine selectivity, expressed, for example, as the ratio IC50 COX-1 : IC50 COX-2. The higher the ratio the greater the selectivity for COX-2. However, a high ratio (of say 50 : 1 or even higher) does not guarantee that at clinical dose rates a drug will inhibit COX-2 with no inhibition of COX-1 in vivo.

Based on selectivity, NSAIDs are classified as nonselective, COX-1 selective, or as preferential or selective (denoting increasing degrees of selectivity) for COX-2 (Table 20.13). Validating, confirming, and interpreting the data in Table 20.13 is problematic, as the scientific literature reports widely differing potency ratios (COX-1 : COX-2) for individual drugs, even in a single species. The in vitro experimental conditions impact markedly on the COX-1 : COX-2 inhibition ratios, with higher values (i.e., higher selectivity for COX-2) commonly obtained when isolated enzyme, broken cell, or intact cell determinations in buffer are used in comparison with whole blood assays. The latter are accepted as the “gold standard” as they approximate most closely to conditions in the whole animal. Thus, Gierse et al. (2002) using isolated enzyme assays, reported for deracoxib an IC50 COX-1 : COX-2 ratio of 380 : 1 in humans and 1295 : 1 in the dog, whereas McCann et al. (2004) for the same drug, in a canine whole blood assay, obtained a ratio of 12 : 1. Likewise, Ricketts et al. (1998) reported a higher COX-1 : COX-2 ratio for rac-carprofen in isolated cell assays than those obtained in whole blood assays (Table 20.14).

Table 20.13 COX inhibitor classificationd

Classification Example Comment
Preferential or selective COX-1 inhibitors Aspirin, ketoprofen (cat)a, vedaprofena, tepoxalin, flunixin (cow) COX-1 inhibitory potency at least 5-fold greater than COX-2 inhibition
Nonselective COX inhibitors S-Carprofen(horse)b, flunixin, ketoprofen(dog, horse)a, meloxicamb, phenylbutazone, tolfenamic acidb, vedaprofena No significant biological or clinical differences in concentrations producing COX-1 and COX-2 inhibition
Slightly or moderately selective COX-2 inhibitorsc S-Carprofen(dog, cat)b, deracoxib, etodolac etoricoxib, meloxicamb, tolfenamic acidb, mavacoxib COX-2 inhibition potency 5- to 30-fold greater than COX-1 inhibition Some antiinflammatory and analgesic activity may be obtained at concentrations inhibiting COX-2 but not COX-1 At higher concentrations, significant inhibition of COX-1 may occur
Highly or very highly selective COX-2 inhibitorsc Cimicoxib, firocoxib, robenacoxib, valdecoxib More than 50-fold greater potency for COX-2 inhibition Limited inhibition of COX-1 in vivo (normally no GI ulceration or antiplatelet effects) even at maximum therapeutic doses

a Differing findings on selectivity from studies in various laboratories. Data in this Table based on whole blood assays.

b Species differences in degree of selectivity for COX-2.

c Selectivity and specificity depend on position and slope of COX-1 and COX-2 inhibition curves and therefore on the level of inhibition considered e.g., IC50, IC80, IC95, etc.

d Ratios of inhibition (COX-1 : COX-2) are markedly affected by experimental conditions, e.g., isolated enzyme versus whole blood assay.

Table 20.14 RS-, S-, and R-carprofen COX-1 : COX-2 IC50 and IC80 ratios in whole blood assays in four species

            IC50 ratio COX- IC80 ratio COX-
Species Enantiomer 1 : COX-2 1 : COX-2
Human1 RS

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Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Analgesic, Antiinflammatory, Antipyretic Drugs

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