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Enzymes involved in the bioconversion of ester-based prodrugs

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ABSTRACT:

Enzymes are essential for the activation of many prodrugs. In this review, the most important enzymes (e.g., paraoxonase, carboxylesterase, acetylcholinesterase, cholinesterase) involved in the bioconversion of ester-based prodrugs will be discussed in terms of their biology and biochemistry. Most of these enzymes fall into the category of hydrolytic enzymes. However, nonhydrolytic enzymes, including cytochrome P450s, can also catalyze the bioconversion of ester prodrugs and thus will be discussed here. Other factors influencing the ability of these enzymes to catalyze the bioconversion of ester-based prodrugs, particularly species and interindividual differences and stereochemical and structural features of the prodrugs, will be discussed. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association

Section snippets

INTRODUCTION

An ideal drug candidate needs to have specific druglike properties, including chemical and enzymatic stability, solubility, low clearance by the liver or kidney, permeation across biological membranes, potency, and safety.1 In addition, drugs and drug formulations need to be “patient friendly,” that is, have minimal frequency of dosing (e.g., once daily), pleasant taste/odor if given orally, and minimal pain if given parenterally. Site-directed delivery of the drug to the target tissue/cell is

Esterases

The classification of esterases is complicated and confusing. While several classification systems exist, none appear to be totally satisfying and universally applied by investigators.

The International Union of Biochemistry and Molecular Biology (IUBMB) divides enzymes into six main categories according to the reactions they catalyze.19 Most enzymes involved in catalyzing the bioconversion of prodrugs belong to class 3–Hydrolyses; that is, carboxylesterases, which have the EC (Enzyme

FACTORS AFFECTING THE BIOCONVERSION OF ESTER PRODRUGS

In the case of prodrugs, the biotransformation in vivo to the active drug determines its ultimate usefulness since the prodrug itself has no pharmacological activity. The rate of biotransformation is particularly important because it plays an important role for the onset (e.g., immediate), duration (e.g., sustained release), and intensity of drug action. For prodrugs designed to increase solubility to promote parenteral use, such as phosphate prodrugs, rapid conversion in the blood is typically

SUMMARY AND CONCLUSION

An overview of the most significant factors and enzymes that dictate the stability of prodrugs in the body has been presented. While some of these factors, such as structural aspects of prodrugs, can be optimized in drug discovery, others are intrinsically related to individuals or certain populations, etc. As such, they create extra uncertainty and add to the complexity of any attempt to predict drug stability. While significant progress has been made in clarifying the mechanisms of how the

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