Species Difference of Esterase Expression and Hydrolase Activity in Plasma

doi:10.1002/jps.23258

Journal of Pharmaceutical Sciences

Volume 101, Issue 10, October 2012, Pages 3979-3988

https://doi.org/10.1002/jps.23258 Get rights and content

ABSTRACT

Differences in esterase expression among human, rhesus monkey, cynomolgus monkey, dog, minipig, rabbit, rat, and mouse plasma were identified using native polyacrylamide gel electrophoresis. Paraoxonase (PON) and butyrylcholinesterase (BChE) were ubiquitous in all species, but were highly expressed in primates and dogs, whereas carboxylesterase (CES) was only abundant in rabbits, mice, and rats. Several unknown esterases were observed in minipig and mouse plasma. These differences in plasma esterases and their expression levels result in species differences with respect to hydrolase activity. These differences were characterized using several different substrates. In contrast to the high hydrolase activity found for p‐nitrophenylacetate (PNPA), a substrate of several hydrolase enzymes, irinotecan, a carbamate compound, was resistant to all plasma esterases. Oseltamivir, temocapril, and propranolol (PL) derivatives were rapidly hydrolyzed in mouse and rat plasma by their highly active CES enzyme, but rabbit plasma CES hydrolyzed only the PL derivatives. Interestingly, PL derivatives were highly hydrolyzed by monkey plasma BChE, whereas BChE from human, dog, and minipig plasma showed negligible activity. In conclusion, the esterase expression and hydrolyzing pattern of dog plasma were found to be closest to that of human plasma. These differences should be considered when selecting model animals for preclinical studies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3979–3988, 2012

Section snippets

INTRODUCTION

Esterified compounds are found everywhere in the human environment, as xenobiotics such as medicines and pesticides or as environmental chemicals and foodstuffs.¹,² Inside the body, these compounds are detoxified or metabolized into nontoxic or active compounds by esterases, mainly in the liver, intestine, and plasma.³,⁴ This characteristic has been utilized in pharmaceutical development in the form of esterified prodrugs. However, plasma esterase activity in humans is markedly different from

Materials

PL derivatives were synthesized as described in Shameem et al.²² from PL hydrochloride (Wako Pure Chemicals, Osaka, Japan). Temocapril and temocaprilat were provided by Daiichi Sankyo Company, Ltd. (Tokyo, Japan). Irinotecan and SN‐38 were donated by Yakult Honsha Company, Ltd. (Tokyo, Japan). Oseltamivir and Ro64‐0802 were kind gifts from Prof. Ogihara (Takasaki University of Health and Welfare, Gunma, Japan). PNPA, α‐naphthylacetate, and bis‐p‐nitrophenyl phosphate (BNPP) were purchased from

Detection of Esterase Activity on Native PAGE Gels

Figure 1 shows the native PAGE gel stained for esterase activity by β‐naphthylacetate in the presence of CaCl₂. Bands corresponding to PON and BChE were observed in the upper part of the gel, whereas albumin and CES bands were seen in the lower part. In the middle part of the gel, undefined bands corresponding to the activity of unknown esterases were observed especially in minipig and mouse plasma.

When the native PAGE gels were stained by β‐naphthylacetate in the absence of CaCl₂, the same

DISCUSSION

In pharmaceutical development, ester compounds are frequently used in the development of prodrugs, either to improve bioavailability, to target a specific organ, or to prevent the adverse effects associated with their parent drugs. Esterase activity in the blood therefore plays an important role in the pharmacokinetics of these prodrugs. Because animal models are used to predict the pharmacokinetics of a prodrug during the preclinical phase, it is important to compare the substrate

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Pharmacokinetics, Pharmacodynamics and Drug MetabolismSpecies Difference of Esterase Expression and Hydrolase Activity in Plasma

ABSTRACT

Section snippets

INTRODUCTION

Materials

Detection of Esterase Activity on Native PAGE Gels

DISCUSSION

J Pharm Sci

Drug Metab Pharmacokinet

Chem Biol Interact

J Biol Chem

Life Sci

Pharmacol Ther

Biochem Pharmacol

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Chem Biol Interact

The mammalian carboxylesterases: From molecules to functions

Annu Rev Pharmacol Toxicol

Human carboxylesterases and their role in xenobiotic and endobiotic metabolism

J Biochem Mol Toxicol

Prodrug approach using carboxylesterase activity: Catalytic properties and gene regulation of carboxylesterase in mammalian tissue

J Pestic Sci

Serum esterases. 1. Two types of esterase (A and B) hydrolyzing p‐nitrophenyl acetate, propionate and butyrate, and a method for their determination

Biochem J

Fractionation of C‐esterase from the Hog's kidney extract

Biochem J

Hydrolytic profile for ester‐ or amide‐linkage by carboxylesterases pI 5.3 and 4.5 from human liver

Biol Pharm Bull

Pharmacokinetics, Pharmacodynamics and Drug Metabolism
Species Difference of Esterase Expression and Hydrolase Activity in Plasma