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Biotransformation and Excretion

The biotransformation of aspirin involves two principally distinct processes that occur in sequence but independent of each other and at different reaction kinetics. They are independently controlled by different enzymes and have a different biological significance: (i) generation of salicylic acid after hydrolytic removal of the acetyl moiety by "Aspirin" esterases and transfer of the acetyl moiety to macro-molecules; (ii) biotransformation(s) of salicylic acid and its metabolites.

Deacetylation of aspirin with subsequent generation of salicylic acid occurs within minutes and, because of the ubiquitous presence of carboxyes-terases, is independent of the aspirin dosage (Section 2.1.1). In contrast, the pharmacokinetics of salicylate, including half-life, volume of distribution, the composition of salicylate metabolites and their fractional excretion are largely determined by the aspirin dosage. The pharmacokinetic parameters of salicylic acid are of particular clinical interest because many of the therapeutic and toxic effects of aspirin, including analgesic, antipyretic effects, and anti-inflammatory actions (Section2.3.2) as well as actions on cell metabolism (Section 2.2.3) and organ toxicity, for example, stomach (Section 3.2.1) and ototoxicity (Section 3.2.4) are caused by salicylic acid. However, the transacetylation of macromolecules by aspirin becomes now increasingly important after the detection of new acetyla-tion targets. The most prominent example is COX-2 that, unlike COX-1, generates a new product 15-(R)-HETE, a precursor of several lipoxins, after acetyla-tion by aspirin. This may be relevant for tissue-protective, anti-inflammatory actions of aspirin as well as nitric oxide (NO) generation via the endo-thelial NO synthase (eNOS) in the cardiovascular system (Section 2.3.2). The elimination of salicy-lates occurs via the kidney, at therapeutic doses predominantly in the form of the glycine conjugation product salicyluric acid [51-54]. Major metabolic pathways of aspirin and salicylic acid, respectively, are summarized in Figure 2.5.

2.1.2.1 Biotransformation of Aspirin

"Aspirin" Esterases Enzymatic hydrolysis ofaspi-rin to the primary metabolite salicylic acid starts already in the gastrointestinal mucosa [55]. It continues in the portal vein blood and liver [56] and eventually reduces the bioavailability of aspirin to about 50% after oral administration of standard preparations. Deacetylation occurs at zero-order kinetics, that is, is independent of the dosage (Section 2.1.1). The plasma half-life of aspirin in men after i.v. administration is about 15-20 min [57].

Aspirin hydrolysis in the systemic circulation is catalyzed by different "aspirin esterases," most notably those in red cells (cytosol) [58, 59] and plasma [46]. This enzyme is located intracellularly in the erythrocyte cytosol, is independent of Ca2+ and other bivalent cations, and unrelated to acetyl-choline esterase [58]. In men, red-cell aspirin esterase accounts for about half of the aspirin hydrolysis activity in vitro [59]. This activity also explains the more than twofold faster aspirin hydrolysis in whole blood in vitro as opposed to plasma [59], -0.5 h versus -1.9 h (Table 2.2).

The other major enzyme activity is plasmatic and associated with the plasma (pseudo)-choline esterase. The aspirin esterase activity and pseudo cho-linesterase activities in plasma (serum) are positively correlated in men but exhibits a skewed distribution [60]. It hydrolyzes aspirin in a manner, different from choline esters [61], requires Ca2+ for optimal activity, and accounts for about 80% of aspirin esterase activity in plasma. The remaining esterase activity in plasma can be attributed to (aryl)-albumin esterase that is acetylated by aspirin [46]. Aspirin esterase activity has also been detected in liver microsomes and other organs, and there it could be separated from cholinesterases and other nonspecific carboxyesterases [62]. Thus, a specific "aspirin" esterase is likely not to be the only enzyme that cleaves aspirin but additional esterases for circulating carboxyesters with broad spectrum substrate specificity might be involved. Studies with radioactive labeled aspirin have shown that a variety

Metabolites

Renal excretion SAG

Metabolites

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