Differences in Esterase Activity to Aspirin and <i>p</i>-Nitrophenyl Acetate among Human Serum Albumin Preparations

Abstract

Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and also hydrolyzes some compounds at both sites. In the present study, we investigated differences in esterase activity among HSA preparations, and also the effects of warfarin, indomethacin, and naproxen on the hydrolytic activities of HSA to aspirin and p-nitrophenyl acetate. The esterase activities of HSA to aspirin or p-nitrophenyl acetate were measured from the pseudo-first-order formation rate constant (k obs ) of salicylic acid or p-nitrophenol by HSA. Inter-lot variations were observed in the esterase activities of HSA to aspirin and p-nitrophenyl acetate; however, the esterase activity of HSA to aspirin did not correlate with that to p-nitrophenyl acetate. The inhibitory effects of warfarin and indomethacin on the esterase activity of HSA to aspirin were stronger than that of naproxen. In contrast, the inhibitory effect of naproxen on the esterase activity of HSA to p-nitrophenyl acetate was stronger than those of warfarin and indomethacin. These results suggest that the administration of different commercial HSA preparations and the co-administration with site I or II high-affinity binding drugs may change the pharmacokinetic profiles of drugs that are hydrolyzed by HSA.

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

“…Previously, we detected low levels of fatty acids in HSA from 090M7001V and SLBD7204V, and fatty acids were not detected in HSA from 113K7601 and 085K7541. 19) These results were also similar to the previous report that hydrolysis of aspirin by HSA containing low levels of fatty acids were noticeably inhibited by warfarin, indomethacin, and naproxen. 19) It is reported that lysine (Lys)-199, histidine (His)-242, and arginine (Arg) -257 are important for the esterase activity to aspirin and the enzymatic activity is facilitated by the simultaneous presence of a deprotonated Lys-199 and a protonated Lys-195.…”

“…19) These results were also similar to the previous report that hydrolysis of aspirin by HSA containing low levels of fatty acids were noticeably inhibited by warfarin, indomethacin, and naproxen. 19) It is reported that lysine (Lys)-199, histidine (His)-242, and arginine (Arg) -257 are important for the esterase activity to aspirin and the enzymatic activity is facilitated by the simultaneous presence of a deprotonated Lys-199 and a protonated Lys-195. 21,22) Fatty acid binding to HSA induces conformational changes, which is changes of surrounding environment by the movement of tyrosine (Tyr)-150 and Arg-257 position on drug pocket of site I, and increases binding of warfarin and aspirin to HSA.…”

“…The hydrolysis of olmesartan medoxomil by HSA was inhibited by warfarin, indomethacin, and naproxen similar to the effects toward aspirin and pnitrophenyl acetate in our previous study. 19) These results were similar to the paper reported by Ma et al 13) which indicated that the hydrolysis of olmesartan medoxomil by HSA was inhibited by warfarin and ibuprofen (site II ligand). Although the hydrolysis of olmesartan medoxomil was inhibited by both sites I and II high affinity drugs, the hydrolysis of olmesartan medoxomil was not inhibited by ethanol.…”

“…Ethanol significantly inhibited hydrolysis of p-nitrophenyl acetate by HSA in all lots. Although ethanol inhibited the 19) hydrolysis by HSA from 113K7601 by 15%, ethanol inhibited hydrolysis by HSA from the other 3 lots by about 50%.…”

“…We previously reported the effect of warfarin and naproxen on the hydrolysis of aspirin and pnitrophenyl acetate by HSA. 19) 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 from 4 different lots of HSA preparations. We also studied the effects of warfarin, indomethacin, and naproxen, which are sites I and II binding drugs, on the hydrolysis of olmesartan medoxomil from 4 different lots of HSA preparations.…”