Aspirin Hydrolysis in Human and Experimental Animal Plasma and the Effect of Metal Cations on Hydrolase Activities

Abstract

The hydrolyzing properties of plasma esterases for aspirin were investigated in human plasma and plasma from experimental animals. The observed rates of aspirin hydrolysis were in the following order: rabbit > human > monkey > rat > mouse > dog > minipig. In human, monkey, and dog plasma, aspirin was hydrolyzed by their major hydrolases, paraoxonase (PON), butyrylcholinesterase (BChE), and albumin. In rabbit, mouse, and rat plasma, carboxylesterase (CES) was determined to be the enzyme responsible for aspirin hydrolysis, and in mouse and rat plasma, especially the latter, hydrolase activity was increased by the addition of ethopropazine, a specific inhibitor of BChE. Interestingly, divalent cations affected the plasma activity by enhancing or inhibiting the hydrolase activity of plasma BChE. The addition of 2 mM calcium increased the hydrolysis of aspirin in human, monkey, and dog plasma by 2.7-, 1.9-, and 2.3-fold, respectively. Magnesium showed a similar but lesser effect. Increasing concentrations of calcium and magnesium resulted in a two-phase stimulatory effect on aspirin hydrolysis in human plasma. In contrast, the addition of zinc had an inhibitory effect on plasma BChE activity. It is postulated that calcium and magnesium bind to BChE and thereby change the conformation of the enzyme to a more appropriate position for aspirin hydrolysis.

A review on gentisic acid as a plant derived phenolic acid and metabolite of aspirin: Comprehensive pharmacology, toxicology, and some pharmaceutical aspects

“…GA is one of the oxidative metabolites of the ASA (a second line metabolite of ASA; Exner et al, 2000). In fact, ASA when absorbed in the acidic environment of the stomach and upper intestine with the oral bioavailability of 40-50% (Pedersen & FitzGerald, 1984), it undergoes hydrolysis in the intestine, liver, and plasma by esterase enzyme to form salicylic acid (SA; Bahar & Imai, 2013) that it is the main and the first active metabolite of ASA (Zaugg, Zhang, Sweedler, & Thormann, 2001). SA undergoes further metabolism in the liver to produce salicyluric acid through conjugation with glycine or glucuronic acid to produce ether and ester glucuronides (Hutt, Caldwell, & Smith, 1986).…”

The antioxidant properties of salicylate derivatives: A possible new mechanism of anti-inflammatory activity

“…17 Salicylic acid is very sensitive to oxidation, as its hydroxylation by liver microsomal hydroxylases forms 2,5-dihydroxybenzoic acid or gentisic acid (2). 18 This compound can react further to produce other hydroxylated derivatives by HO Å attack. 19 Consequently, it is likely that the in vivo concentration of aspirin and related salicylates decreases as a result of hydrolysis and aromatic hydroxylation.…”

Effects of Alcohol on Human Carboxylesterase Drug Metabolism

“…Aspirin is nearly completely absorbed after oral administration and the bioavailability ranges from 50-68% due to a high degree of first-pass metabolism. A recent paper found that butyrylcholinesterase (BChE) is the major responsible enzyme for aspirin hydrolysis in plasma [48]. However, the hydrolysis of aspirin by human plasma was undetectable as compared with efficient hydrolysis in intestinal microsomes [43].…”

“…In humans, aspirin is rapidly absorbed after oral administration [50]. Once absorbed, it undergoes hydrolysis by several plasma esterases including butyrylcholinseterase, paraoxonase, albumin, and platelet-activating factor acetylhydrolase [48, 51]. Therefore, we focused on the AUC 0→2h as it would more precisely characterize the effect of alcohol on aspirin hydrolysis by intestinal CES2 since aspirin plasma concentrations at later time points could be affected by plasma esterase activity.…”