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Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate.
Eur J Pharm Sci 2002; 16(4-5):297-304EJ

Abstract

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, School of Pharmacy, Trinity College, 2, Dublin, Ireland. gilmerjf@tcd.ieNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12208460

Citation

Gilmer, John F., et al. "Isosorbide-based Aspirin Prodrugs. II. Hydrolysis Kinetics of Isosorbide Diaspirinate." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 16, no. 4-5, 2002, pp. 297-304.
Gilmer JF, Moriarty LM, Lally MN, et al. Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate. Eur J Pharm Sci. 2002;16(4-5):297-304.
Gilmer, J. F., Moriarty, L. M., Lally, M. N., & Clancy, J. M. (2002). Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 16(4-5), pp. 297-304.
Gilmer JF, et al. Isosorbide-based Aspirin Prodrugs. II. Hydrolysis Kinetics of Isosorbide Diaspirinate. Eur J Pharm Sci. 2002;16(4-5):297-304. PubMed PMID: 12208460.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate. AU - Gilmer,John F, AU - Moriarty,Louise M, AU - Lally,Maeve N, AU - Clancy,John M, PY - 2002/9/5/pubmed PY - 2003/4/15/medline PY - 2002/9/5/entrez SP - 297 EP - 304 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 16 IS - 4-5 N2 - Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate. SN - 0928-0987 UR - https://www.unboundmedicine.com/medline/citation/12208460/Isosorbide_based_aspirin_prodrugs__II__Hydrolysis_kinetics_of_isosorbide_diaspirinate_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928098702001240 DB - PRIME DP - Unbound Medicine ER -