**3.2 Distribution**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

hydrolase of human blood [18].

colorectal cancer [20].

process [21].

transit time.

inhibition compared to oral dosing [19].

aspirin rather than salicylic acid. A complete picture of absorption track of aspirin is represented in **Figure 4** [16]. Approximately 70% of aspirin reaches the peripheral circulation intact with maximum serum concentrations observed at 25 min after administration. After entering the bloodstream, aspirin undergoes enzymatic hydrolysis to yield acetate and salicylic acid. The major enzymes hydrolyzing aspirin in plasma are believed to be cholinesterases [17]. Acetylhydrolase-I, an intracellular erythrocyte platelet-activating factor, has been characterized as the major aspirin

Intravenous aspirin has a distribution half-life of about 3 min and inhibits prostaglandin biosynthesis within 5 min of administration, reflecting the rapid onset of

Recent studies by Lichtenberger et al. demonstrated that aspirin could enter the lymph fluid directly when administered intragastrically or intraduodenally, potentially increasing its pharmacologic activity as a chemopreventive agent for

Rectal absorption of salicylate is also possible and cutaneous absorption may occur from salicylate containing rubefacients. Following oral administration of an aqueous solution, the absorption kinetics of aspirin is found to follow a first-order

The factors affecting absorption of salicylate are Rate of gastric emptying volume of food, pH of stomach contents, nervous state, concurrent drugs, exercise, posture, formulation and Disease states associated with altered gastrointestinal

**26**

**Figure 4.**

*In vivo reaction of aspirin.*

Once absorbed, salicylates are distributed extensively through body fluids. Reported values for the apparent volume of distribution (Vd) of salicylate range from 9.6 to 12.7 L in adults with similar values (0.12–0.14 L/kg) in children [22].

Both aspirin and salicylic acid are partially bound to serum proteins. The distribution of aspirin is further enhanced by binding to human serum albumin [23, 24]. Human serum albumin is the most abundant protein found in blood and is often used as a plasma shuttle for steroids, hormones, and other small molecules. Binding studies suggest a conformational change in albumin upon acetylation that can influence transport and metabolism of other critical metabolites and drugs. For example, aspirin-induced acetylation of albumin can inhibit glucose binding [25], while increasing the binding of other molecules, as observed with the increased affinity of acetylated albumin for the marker anion acetrizoate [26]. Aspirin's pharmacodynamic is also influenced by the interaction of other metabolites and serum albumin [24]. However, aspirin acetylation of serum albumin likely inhibits the binding of other metabolites commonly transported by albumin. In vitro studies have shown serum albumin binding and acetylation is dependent upon fatty acid binding, pH and temperature [27].

**Figure 5.** *Reactivity of aspirin in different biological environments of proteins.*

Both salicylic acid and aspirin have been found to diffuse slowly into the cerebrospinal fluid (CSF) due to the high degree of ionization of salicylic acid at the pH (7.4) of plasma. Salicylic acid readily crosses the placenta, fetal plasma concentrations being higher at birth than concurrent maternal concentrations [28].

#### **3.3 Metabolism and excretion**

Aspirin is rapidly converted to salicylic acid with a half-life of only 15–20 minutes [19]. This hydrolysis is due to nonspecific esterases found in many body. The acetyl component of aspirin after oral and intravenous dosing is found in gastric mucosal cells or is excreted as carbon dioxide after passing through the Krebs cycle [29]. During absorption, aspirin esterase activity in the gastrointestinal mucosal membranes contributes 28–35% of the hydrolysis of aspirin; though the activity of esterase enzyme may vary in relation to age and gender. Aspirin esterase activity is reduced in patients with alcoholic liver disease [17].

The major route of elimination of aspirin is through its hydrolyzed product salicylic acid. Salicylic acid is cleared from circulation via the kidneys with a serum half-life of approximately 2 h. A summary of the most common reactions of aspirin in biological systems are summarized in **Figure 5**.

Salicylic acid is partly excreted unchanged and partly metabolized. Free salicylic acid diffuses readily across the glomerulus and is also actively secreted by the proximal tubule. The conjugates of salicylic acid are also excreted via kidney, being dependent on glomerular filtration and tubular secretion. The hydroxylated metabolite gentisic acid is excreted in the same way as free salicylic acid [30].

#### **4. Pharmacodynamics of aspirin**

The most recognized mechanism of action of aspirin is to inhibit the synthesis of prostaglandins but this by itself does not explain the repertoire of anti-inflammatory effects of aspirin. Later, another mechanism was described: the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid by acetylation of the enzyme cyclooxygenase-2. The availability of a stable analog of ATL has stimulated investigations on the use of this analog and it has been found that, similar to endogenously produced lipoxins, ATL resolves inflammation and acts as antioxidant and immunomodulator. If we consider that in PE and in the obstetric APS, there is an underlying inflammatory process; aspirin might be used based on the induction of ATL [31].

The COX-inhibitory activity of aspirin is contingent on the administered dose. Low doses, those ranging from 75 to 300 mg, result in selective inhibition in platelet TXA2 production without suppressing prostacyclin (PGI2), a common platelet antagonist and vasodilator. PGI2 is expected to be derived mainly from vascular COX-2 suggesting that COX- 2 inhibition is minimal in the low-dose regime. Increased doses (>1200 mg) have analgesic and anti-inflammatory properties, properties associated with the pathophysiological inhibition of COX-1 and COX-2. It is important to note that COX- 2 can also utilize arachidonic acid for synthesis of lipoxins, particularly 15-hydroxyeicosatetraenoic acid [32, 33]. It is unlikely that the COX-2 is more than 5% acetylated while platelet-derived COX-1 is likely to be >70% acetylated. This suggests that regular low-dose aspirin will invariably maintain COX-1 inhibition in circulating platelets, with minimal effect in the inhibition of peripheral COX-2 [34].

A summary of the pharmacodynamic action of aspirin is summarized in **Figure 6** [35, 36].

**29**

*Risk-Benefit Events Associated with the Use of Aspirin for Primary Prevention…*

*DOI: http://dx.doi.org/10.5772/intechopen.93286*

**5. Pharmacological action of aspirin**

Beneficial clinical impaction of aspirin is mainly anti-inflammatory and anti-pyretic action. Evidence suggests that aspirin is a better analgesic than salicylic acid [37, 38]. The analgesia produced by aspirin is dose-dependent, although

The generally accepted therapeutic plasma concentration range of salicylate for the treatment of chronic inflammatory disease is 15–30 mg/100 ml (150–300 mg/L

Other indications for aspirin use are angina pectoris, angina pectoris prophylaxis, ankylosing spondylitis, cardiovascular risk reduction, colorectal cancer, ischemic stroke, ischemic stroke (prophylaxis), myocardial infarction, myocardial infarction (prophylaxis), osteoarthritis, revascularization procedures (prophy-

The most common side effect of aspirin is gastrointestinal upset ranging from

the response does not parallel serum aspirin concentrations [39]. The dose of aspirin required for its antipyretic action is less than that required for

or 1–2 mmol/L), requiring daily doses in excess of 3 g [41].

laxis), rheumatoid arthritis and systemic lupus erythematosus [42].

gastritis to gastrointestinal bleed. Other adverse effects are as followed:

**5.1 Therapeutic effects**

*Pharmacodynamics of aspirin.*

analgesia [40].

**Figure 6.**

**5.2 Adverse effects**

*Risk-Benefit Events Associated with the Use of Aspirin for Primary Prevention… DOI: http://dx.doi.org/10.5772/intechopen.93286*


**Figure 6.**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

being higher at birth than concurrent maternal concentrations [28].

**3.3 Metabolism and excretion**

patients with alcoholic liver disease [17].

**4. Pharmacodynamics of aspirin**

based on the induction of ATL [31].

of peripheral COX-2 [34].

**Figure 6** [35, 36].

in biological systems are summarized in **Figure 5**.

Both salicylic acid and aspirin have been found to diffuse slowly into the cerebrospinal fluid (CSF) due to the high degree of ionization of salicylic acid at the pH (7.4) of plasma. Salicylic acid readily crosses the placenta, fetal plasma concentrations

Aspirin is rapidly converted to salicylic acid with a half-life of only 15–20 minutes [19]. This hydrolysis is due to nonspecific esterases found in many body. The acetyl component of aspirin after oral and intravenous dosing is found in gastric mucosal cells or is excreted as carbon dioxide after passing through the Krebs cycle [29]. During absorption, aspirin esterase activity in the gastrointestinal mucosal membranes contributes 28–35% of the hydrolysis of aspirin; though the activity of esterase enzyme may vary in relation to age and gender. Aspirin esterase activity is reduced in

The major route of elimination of aspirin is through its hydrolyzed product salicylic acid. Salicylic acid is cleared from circulation via the kidneys with a serum half-life of approximately 2 h. A summary of the most common reactions of aspirin

Salicylic acid is partly excreted unchanged and partly metabolized. Free salicylic acid diffuses readily across the glomerulus and is also actively secreted by the proximal tubule. The conjugates of salicylic acid are also excreted via kidney, being dependent on glomerular filtration and tubular secretion. The hydroxylated metabolite gentisic acid is excreted in the same way as free salicylic acid [30].

The most recognized mechanism of action of aspirin is to inhibit the synthesis of prostaglandins but this by itself does not explain the repertoire of anti-inflammatory effects of aspirin. Later, another mechanism was described: the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid by acetylation of the enzyme cyclooxygenase-2. The availability of a stable analog of ATL has stimulated investigations on the use of this analog and it has been found that, similar to endogenously produced lipoxins, ATL resolves inflammation and acts as antioxidant and immunomodulator. If we consider that in PE and in the obstetric APS, there is an underlying inflammatory process; aspirin might be used

The COX-inhibitory activity of aspirin is contingent on the administered dose. Low doses, those ranging from 75 to 300 mg, result in selective inhibition in platelet TXA2 production without suppressing prostacyclin (PGI2), a common platelet antagonist and vasodilator. PGI2 is expected to be derived mainly from vascular COX-2 suggesting that COX- 2 inhibition is minimal in the low-dose regime. Increased doses (>1200 mg) have analgesic and anti-inflammatory properties, properties associated with the pathophysiological inhibition of COX-1 and COX-2. It is important to note that COX- 2 can also utilize arachidonic acid for synthesis of lipoxins, particularly 15-hydroxyeicosatetraenoic acid [32, 33]. It is unlikely that the COX-2 is more than 5% acetylated while platelet-derived COX-1 is likely to be >70% acetylated. This suggests that regular low-dose aspirin will invariably maintain COX-1 inhibition in circulating platelets, with minimal effect in the inhibition

A summary of the pharmacodynamic action of aspirin is summarized in

**28**

*Pharmacodynamics of aspirin.*
