**2. Chemistry of aspirin**

Production of aspirin is completed as single chain reaction. Acidic and alkaline both medium are suitable for synthesis. In chemistry language, aspirin is produced by the mixing of salicylic acid and acetic anhydride with the aid of phosphoric acid. Acetylsalicylic acid possesses three functional groups, namely hydroxyl, acetyl and ester. It is due to the presence of hydroxyl group polarity index of salicylic acid is high than that of aspirin. The reaction equation is displayed (**Figure 2**) [4].

#### **Figure 2.** *Production reaction.*

Aspirin is an O-acetyl derivative of salicylic acid (ASA—acetylsalicylic acid) and its dominant mechanism of action is believed to be through the transfer of this acetyl group to (▬OH) and amino (▬NH2) functionalities present in biological macromolecules as depicted in **Figure 3**. The acyl ester group is also unstable under basic conditions, and its hydrolysis to acetate is believed to proceed by a general base-assisted mechanism as described previously [5, 6]. More recent computational studies have suggested an n→π\* interaction between the aromatic carboxylic acid and the carbonyl carbon of the acetate group [7]. This is consistent with a nuclear magnetic resonance spectroscopy (NMR) study [8]**,** which posits the formation of a cyclic hemi-orthoester under basic conditions which can rearrange to give either the parent aspirin anion or a mixed anhydride.

Although the prevalence and role of the mixed anhydride in the biochemistry of aspirin has yet to be determined, the broad scope of anhydride reactivity may help to explain promiscuous acetylation activity of aspirin in biological systems [9, 10].

**25**

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

Interestingly, it has also been shown that the mixed anhydride can react with the primary amino group of glycine in organic solvents to form N-salicyloylglycine, suggesting a second class of aspirin-mediated protein modifications [11]. The nonselectivity of aspirin-mediated acetylation was demonstrated by Richard Farr and co-workers in 1968 [12]. In these experiments, aspirin labeled with 14C at the acetyl carbonyl carbon was incubated with a series of blood proteins as well as common enzymes and nucleic acids. Following dialysis, substantial radiolabeling of albumin, immunoglobulins, α-macroglobulin, and other enzymes was observed. More recent mass spectrometrybased studies have validated this initial finding and the list of proteins acetylated by aspirin has grown to include histones, IKKβ (I-kappa-β-kinase beta), and many others [13]. At high concentrations (micromolar to millimolar), aspirin has been shown to react with nucleophilic groups on proteins resulting in irreversible acetylation. These include the functional groups of the residues lysine (▬NH2), arginine (▬NH2), serine (▬OH), threonine (▬OH), tyrosine (▬OH), and cysteine (▬SH) [31, 32]. Synthesis of 13C- or 14C-labeled aspirin has also facilitated the real-time analysis of acetylation of

After absorption, as acetylsalicylic acid is rapidly converted to salicylic acid by hydrolysis and first-pass metabolism, peak plasma concentrations of acetylsalicylic acid are extremely sensitive to minor variations in solid dosage form dissolution and disintegration. In contrast, plasma concentrations of salicylic acid are predictable

Absorption of salicylate occurs rapidly by passive diffusion of un-ionized lipophilic molecules from the stomach at the low pH of the milieu. Aspirin (pKa 3.5) and salicylic acid (pKa 3.0) are weak acids, being 99% un-ionized at pH 1 and able to diffuse through lipid membranes. Less rapid absorption is observed with other formulations due to the rate limiting step of tablet disintegration; this latter factor being maximal in alkaline pH. Although aspirin can spontaneously hydrolyze, this is slow so that there is little or no free salicylate in the intestine and it is absorbed as

ubiquitin, hemoglobin, and human serum albumin [14].

**3. Pharmacokinetics of aspirin**

and relatively stable [15].

**3.1 Absorption**

**Figure 3.**

*Chemical reaction at molecular level.*

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

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

**Figure 3.** *Chemical reaction at molecular level.*

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

Aspirin is an O-acetyl derivative of salicylic acid (ASA—acetylsalicylic acid) and its dominant mechanism of action is believed to be through the transfer of this acetyl group to (▬OH) and amino (▬NH2) functionalities present in biological macromolecules as depicted in **Figure 3**. The acyl ester group is also unstable under basic conditions, and its hydrolysis to acetate is believed to proceed by a general base-assisted mechanism as described previously [5, 6]. More recent computational studies have suggested an n→π\* interaction between the aromatic carboxylic acid and the carbonyl carbon of the acetate group [7]. This is consistent with a nuclear magnetic resonance spectroscopy (NMR) study [8]**,** which posits the formation of a cyclic hemi-orthoester under basic conditions which can rearrange to give either the

Although the prevalence and role of the mixed anhydride in the biochemistry of aspirin has yet to be determined, the broad scope of anhydride reactivity may help to explain promiscuous acetylation activity of aspirin in biological systems [9, 10].

**24**

**Figure 1.**

**Figure 2.** *Production reaction.*

*First container of aspirin.*

parent aspirin anion or a mixed anhydride.

Interestingly, it has also been shown that the mixed anhydride can react with the primary amino group of glycine in organic solvents to form N-salicyloylglycine, suggesting a second class of aspirin-mediated protein modifications [11]. The nonselectivity of aspirin-mediated acetylation was demonstrated by Richard Farr and co-workers in 1968 [12]. In these experiments, aspirin labeled with 14C at the acetyl carbonyl carbon was incubated with a series of blood proteins as well as common enzymes and nucleic acids. Following dialysis, substantial radiolabeling of albumin, immunoglobulins, α-macroglobulin, and other enzymes was observed. More recent mass spectrometrybased studies have validated this initial finding and the list of proteins acetylated by aspirin has grown to include histones, IKKβ (I-kappa-β-kinase beta), and many others [13]. At high concentrations (micromolar to millimolar), aspirin has been shown to react with nucleophilic groups on proteins resulting in irreversible acetylation. These include the functional groups of the residues lysine (▬NH2), arginine (▬NH2), serine (▬OH), threonine (▬OH), tyrosine (▬OH), and cysteine (▬SH) [31, 32]. Synthesis of 13C- or 14C-labeled aspirin has also facilitated the real-time analysis of acetylation of ubiquitin, hemoglobin, and human serum albumin [14].
