Stabilization of the dipropionate ester of DHPG, 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine against enzymatic hydrolysis using eomplexation

Abstract The diester of 9-[(1,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) undergoes enzymatic hydrolysis in the presence of rat and monkey intestinal homogenate forming the more polar compound DHPG which has diminished membrane permeability. The effects of various complexing agents on the enzymatic hydrolysis of the diester in the presence of rat and monkey intestinal homogenate were evaluated. Benzyl alcohol and salicylic acid derivatives caused a 2.8–7.2-fold enhancement in the stability of the diester. Solubility studies in the presence of these ligands indicated formation of 1:1 and 1:2 complexes with improved solubilities. Inhibition kinetic experiments were conducted using purified porcine liver esterase. The inhibition type, and the values of the kinetic parameters for benzyl alcohol and gentisic acid were determined from Lineweaver-Burk plots. These plots indicated competitive and mixed (combination of competitive and non competitive) inhibition for gentisic acid and benzyl alcohol, respectively. The competitive inhibition has been explained as complex formation between the inhibitor and the substrate. Thus co-administration of the diester and the complexing agent would protect the diester against enzymatic degradation during its residence time in GI tract.