Synthesis, Characterization, and In Vitro Conversion Kinetics of Novel Atorvastatin Prodrugs
Date
2022-12-20
Authors
Buthaina Amjad Taleb Al-Jubeh
بثينة أمجد طالب الجعبة
Journal Title
Journal ISSN
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Publisher
Al-Quds University
Abstract
Hypercholesterolemia is a risk factor for the development of atherosclerotic disease. Atorvastatin is a mainstay in the prevention and treatment of hypercholesterolemia and atherosclerotic cardiovascular disease. Atorvastatin efficiently lowers increased plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Due to significant presystemic metabolism, atorvastatin has low oral bioavailability (14 %). By transiently modifying the structure of a substance via prodrug synthesis, low bioavailability, and other pharmacokinetic and/or physicochemical disadvantages, can be resolved. The synthesis of novel atorvastatin prodrugs as possible candidates for atorvastatin delivery with improved bioavailability and fewer side effects is described in this thesis. Based on Bruice's enzyme model of intramolecular reactions, three atorvastatin prodrugs were synthesized in high yield by conjugating dicarboxylic anhydride linkers (maleic anhydride, succinic anhydride, and phthalic anhydride) to the hydroxyl groups of atorvastatin; in order to create prodrug systems with intramolecular hydrolysis ability. The prodrugs are expected to have greater bioavailability, because they hide the metabolically labile functional groups, and increased water solubility. Melting point, FT-IR, LC-MS, and 1H-NMR analyses were used to confirm the identity of the produced prodrugs. The intramolecular hydrolysis of the three prodrugs in different media was studied in vitro and found to have varying conversion rates or no conversion. The prodrug containing the maleate linker (proD1) was completely hydrolyzed in 0.1N acid solution, pH 3 buffer, and human plasma, at half-lives of 102 hours, 161 hours, and 198 hours, respectively. The succinate-linked prodrug (proD2) was degraded in acidic medium exclusively (pH 3) and had a half-life of 216 hours. The pH of the medium influenced prodrug intraconversion, which was quicker in acidic conditions. Furthermore, prodrug intraconversion was dependent on the structural characteristics of the connected prodrug linker,
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and the intramolecular reaction was achieved in a strained prodrug system with a favorable proximity orientation.