Aspirin (ASA) has been used widely in the prophylaxis of thromboembolic disease because of its irreversible anti-platelet aggregative effect; however, this effect is lost following its hydrolysis to salicylic acid (SA) by ASA esterases. ASA undergoes significant first-pass elimination in both the gastrointestinal tract and liver and in the present study ASA esterase activity in the rabbit intestinal tract has been examined in vitro. Both subcellular location and distribution along the intestinal tract were studied. In the small intestine ASA esterase activity was located principally in the microsomal and cytosolic fractions while in the large intestine activity was predominantly cytosolic. However, total activity in the large intestine was 10-100 fold lower than in the small intestine. When ASA esterase activity along the length of the small intestine was examined in detail, apparent V(max) values for the microsomal esterase decreased aborally from 315 nmol SA mg protein-1 min-1 in the duodenum to 85 nmol SA mg protein-1 min-1 in the terminal ileum while V(max) for the cytosolic esterase in the same segments was lower and less variable (32-75 nmol SA mg protein-I min-1). The respective apparent K(m) values for both microsomal and cytosolic esterases were similar throughout the small intestine although the absolute value for apparent K(m) of the microsomal esterase (4.11 +/- 1.38 mM) was significantly (p <0.05) greater than that of the cytosolic enzyme (2.43 +/- 0.21 mM). Total ASA esterase activity in the small intestine also decreased aborally. The data indicate that different isozymes of ASA esterase may occur in the microsomal and cytosolic fractions. Moreover, the K(m) values are such that the enzymes would be expected to have a marked influence on the systemic availability of ASA only at low doses. Our study suggests that a knowledge of inter- and intra-individual variability in intestinal esterase activity in man may be critical for the development of reliable anti-thromboembolic oral dose formulations of ASA.
|Journal||Asia Pacific Journal of Pharmacology|
|Publication status||Published - 1992|