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BioFiles Volume 6, Number 1 — Drug Metabolism

Download BioFiles v6 n1 (3.2 Mb PDF)

 

Drug MetabolismTable of Contents

  • Introduction
  • Drug Transport: Proteins, Antibodies, and Modulators
  • Phase 1 Drug Metabolism: Enzymes, Substrates, and Antibodies
  • Drug Conjugate Analysis: Enzymes, Substrates and Inhibitors, and Derivitization Reagents 

 


Introduction

Robert Gates
Robert Gates

In the past two decades, designers of new drugs have employed the increasing body of knowledge of how drugs are absorbed, distributed, metabolized, and excretedthe ADME concept-to optimize drug efficacy. Small molecule organic drugs are considered xenobiotics-compounds foreign to our native metabolome. Most require enzymatic modification for detoxification and elimination. This enzymatic modification (biotransformation) occurs by two types of reactions, phase I and phase II, which differ regarding the type of modification introduced. Biotransformation is also utilized in the metabolism of many prodrugs to their active form, for example enalapril to enalaprilate. Understanding and manipulating these enzyme/proteinbased metabolic mechanisms is an area of increasing focus for improved drug targeting to specific organs, tissues, and cell types, as well as enabling creative strategies for improving bioavailability and circulating time.

An added complexity for drug designers is the effect of human polymorphisms of metabolic enzymes on drug metabolism. Several metabolic enzymes have known common polymorphisms that result in either altered enzymatic activity or protein stability. A classic example of differing pharmacogenetics and drug efficacy, is codeine. Codeine is a prodrug that is modified by cytochrome P450 (CYP2D6) to morphine. The CYP2D6 locus is highly polymorphic and approximately 6–10% of the population either lacks or exhibits little CYP2D6 enzymatic activity. These poor responders do not effectively metabolize codeine and exhibit little analgesic effect following codeine administration. Ultra-rapid metabolizers, who may constitute 4% of the population, may develop opioid intoxication following codeine administration. A challenge for drug designers will be to integrate the increasing body of information provided by the field of pharmacogenetics to create safer drugs with lower risks of adverse drug reaction.

This issue of Biofiles is devoted to our diverse portfolio of reagents, enzymes, and labware designed for the analysis of drug delivery, absorption, and metabolism.

Specific product focus for this issue is drug transport, phase I enzymes, and drugcongugate analysis.

  • Our portfolio of drug transport-related products includes transporter protein/ membrane preparations as well as selected antibodies and modulators to transport proteins.
  • Our phase I metabolism products include enzymes such as cytochrome P450s and related electron transport proteins, other oxidases, and a select list of related antibodies.
  • Drug conjugate analysis focuses mainly on sample preparation, hydrolysis, derivitization, and subsequent analysis of glucuronide and sulfate conjugates.

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