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Overview

Predicting Population Variability and Drug-drug Interactions

Look to Corning® GentestSM Contract Research Services to perform comprehensive or fit for purpose reaction phenotyping studies—including custom-designed approaches as necessary—that identify the number and type of enzymes responsible for drug clearance. This includes:

• Reaction Phenotyping Services – CYP
• Reaction Phenotyping Services – CES
• Reaction Phenotyping Services – UGT

Identification of the specific CYP/ CES/UGT enzyme involved in the metabolism of a specific drug candidate is useful for:

  • Predicting population variability: If a drug is principally metabolized by a single enzyme (particularly one exhibiting polymorphism), population variability in rates of metabolism may be high. Similarly, if a drug is principally metabolized by an enzyme that is inducible, population variability in rates of metabolism may also be high.
  • Predicting drug-drug interactions: If a drug is principally metabolized by a single enzyme, competition by other drugs for metabolism by this enzyme may cause a drug-drug interaction. Similarly, if a drug is principally metabolized by an enzyme that is inducible, co-administration of a drug which induces this enzyme may also cause a drug-drug interaction.

High Througput Reaction Phenotyping

Reaction Phenotyping Services

Cytochrome P450 (CYP) Enzyme Reaction Phenotyping

Corning Gentest Contract Research Services utilizes multiple methods to determine which cytochrome P450 enzyme(s) is principally responsible for the metabolism of a new chemical entity (NCE). These include:

  • Assessment of test article metabolism using individual, cDNA-expressed human cytochrome P450 enzymes
  • Inhibition of specific cytochrome P450 enzymes with selective chemical and immunochemical (antibody) inhibitors
  • Analysis of enzyme kinetic parameters using individual, cDNA-expressed human cytochrome P450 enzymes and human liver and intestinal microsomes
  • Correlation of the rates of metabolism for marker, enzyme-selective activity in a panel of characterized human liver microsomes

Carboxylesterase (CES) Reaction Phenotyping

Carboxylesterases (CES) can be the principal means of metabolism of many pharmaceuticals and endobiotics. These enzymes are also well-known to catalyze conversion of pro-drugs to the active drug. Two major members of this family are:

  • Human CES1, expressed as two major isoforms, CES1b and CES1c. CES1 protein is expressed in many organs, especially in the liver, but its expression in the gastrointestinal tract is markedly low.
  • CES2 protein, also expressed in many extra-hepatic tissues, especially the gastrointestinal tract and at lower levels in the liver.

CES1 preferentially hydrolyzes substrates that, upon hydrolysis, yield a small alcohol group and larger acyl group, whereas CES2 prefers substrates that yield a larger alcohol group and smaller acyl group. To support your requirements, Corning Gentest Contract Research Services can provide reaction phenotyping procedures to determine the role of CES1 and CES2 in the metabolism of a selected test article.

Uridine Diphosphoglucuronosyl Transferase (UGT) Reaction Phenotyping

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymes are often the principal means of metabolism of many pharmaceuticals. Some human cytochrome UGT enzymes are polymorphic with a significant percentage of populations being deficient in a specific enzyme (e.g., UGT1A1). Other human UGT enzymes are induced by certain environmental exposures or drug treatments. The expression levels of specific UGT enzymes vary substantially among individuals. To support your requirements, Corning Gentest Contract Research Services can provide a variety of reaction phenotyping procedures to determine the role of UGT enzymes in the metabolism of a selected test article.

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Reaction Phenotyping Example Study Outlines