Rate and equilibrium constants for acid-catalyzed lactone hydrolysis of HMG-CoA reductase inhibitors

Abstract

The acid-catalyzed hydrolysis of mevalonolactone and several structurally related hypocholesterolemic agents was studied in a pH 2.0 buffer at 37°C. All of the reactions exhibited pseudo first-order kinetics from which the equilibrium constant and rate constants for hydrolysis and lactonization were derived. Except for mevalonic acid lactone, all of the compounds reacted at essentially the same rate. Mevalonolactone hydrolyzes at a rate similar to the other compounds but relactonizes at a substantially faster rate; variable temperature kinetic studies indicate that this difference is due to both enthalpic and entropic factors. The hydrolysis data are used to simulate the extent of drug degradation that occurs in acidic gastric fluids following oral administration of these drugs.