The Effect of Ethanol on the Hydrolysis of Ester-Type Drugs by Human Serum Albumin

Abstract

Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type drugs with other drugs by HSA has been reported, there are only a few studies concerning the effect of pharmaceutical excipients on the hydrolysis of ester-type drugs by HSA. In the present study, we investigated the effect of ethanol (2 vol%; 345 mM) on the hydrolysis of aspirin, p-nitrophenyl acetate, and olmesartan medoxomil, which are ester-type drugs, with 4 different lots of HSA preparations. The hydrolysis activities of HSA toward aspirin, p-nitrophenyl acetate, and olmesartan medoxomil were measured from the pseudo-first-order degradation rate constant (k obs ) of salicylic acid, p-nitrophenol, and olmesartan, respectively, which are the HSA-hydrolyzed products. Ethanol inhibited hydrolysis of aspirin by HSA containing low levels of fatty acids, but not by fatty acid-free HSA. Ethanol inhibited hydrolysis of p-nitrophenyl acetate by both fatty acid-free HSA and HSA containing low levels of fatty acids. In contrast, the hydrolysis of olmesartan medoxomil by HSA was insignificantly inhibited by ethanol, but inhibited not only by warfarin and indomethacin but also by naproxen, which are site I binding drugs and a site II binding drug, respectively. These results suggest that the inhibitory action of ethanol on the hydrolysis of ester-type drugs by HSA differs between site I binding drugs and site II binding drugs.Key words human serum albumin; ethanol; hydrolysis; olmesartan medoxomil; aspirin; drug interaction Human serum albumin (HSA) is a monomeric, 585-residue protein, and contains three structurally similar α-helical domains (I-III); each domain is divided into subdomains A and B, which contain six and four α-helices, respectively.

High‐Fidelity End‐Functionalization of Poly(ethylene glycol) Using Stable and Potent Carbamate Linkages

“…Considering the use of self-assembled nanostructures as drug nanocarriers, we further evaluated the stability of self-assembled nanostructures against esterase, which is abundant in biological fluids such as blood serum. [22] For direct comparison and clarity of GPC data interpretation, spherical micelles self-assembled from mPEG 45 -Carbamate-PS 6 and mPEG 45 -Ester-PS 6 BCPs were examined. Upon incubating the micellar dispersion with esterase for 0-120 h, esterase-mediated degradation of mPEG 45 -Ester-PS 6 amphiphiles were clearly apparent, as evidenced from time-dependent GPC elution traces (Figure 4 g).…”