**3. Pharmacokinetics of aspirin**

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 and relatively stable [15].

#### **3.1 Absorption**

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

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 hydrolase of human blood [18].

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 inhibition compared to oral dosing [19].

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 colorectal cancer [20].

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 process [21].

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 transit time.

**27**

**Figure 5.**

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

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

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

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

binding, pH and temperature [27].

**3.2 Distribution**

**Figure 4.** *In vivo reaction of aspirin.*

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