cyprotex
the ADME Tox specialists

gADME™ (Genomic ADME)

 

Customer Testimonial
"We were interested in assessing whether a lead molecule exhibited any polymorphic liability of CYP2D6 enzyme. We approached Apredica, a Cyprotex company, to collaboratively design a study protocol that would address this question. Our compound and control were screened by gADME™, a novel technology that allows evaluation of the effect of enzyme polymorphism on drug metabolism. In contrast to the reference compound, which exhibited considerable variability in intrinsic clearance due to the impact of CYP2D6 polymorphism, less variability was observed among several key CYP2D6 alleles for our molecule. These studies increased our confidence to progress this compound. We feel gADME™ is a valuable tool in characterizing key drug-metabolizing enzymes. It has the potential to improve selection of drug candidates, and to help design better clinical trials and/or dosing strategies."

Repligen Corporation

Cyprotex’s gADME™ service combines genomic information about drug metabolizing enzymes (DMEs) with ADME. It evaluates the potential of a panel of DME preparations, including genetic variants of enzymes, to metabolize new chemical entities.

gADME™ in vitro screen generates information about drug clearance, its half-life, percentage of activity compared to wild type of the enzyme of interest and a chosen control substrate, as well as the percentage of compound remaining at each time-point tested.

In addition to the screening service, we also offer baculovirus clones and other clones that can be used to generate antibodies for phenotyping studies.

Contact us to learn more about how Cyprotex’s gADME™ can help your drug development efforts.

 

Genetic Polymorphisms

To date, over 30 DMEs are known to be implicated in drug metabolism and many of these enzymes are polymorphic1. Mutant alleles or single nucleotide polymorphisms occur with a frequency of at least 1-2% in the general population and include copy number variants, mutations, insertions and deletions. These polymorphisms generally results in either reduced or enhanced activity of the enzyme. Genetic polymorphisms in drug metabolism cause pharmacokinetic variability in vivo, which can result in either adverse drug reactions (ADRs) due to toxicity or lack of drug efficacy in humans. The ADRs have on rare occasions resulted in deaths, and have been linked to increased hospital admissions thus adding burden to an already challenged healthcare system. Additionally, more than half of the drugs cited in ADR studies are metabolized by polymorphic Phase I enzymes, with polymorphisms in cytochrome P450 enzymes accounting for the majority of ADRs2. Specifically, the cytochrome P450 enzymes, such as CYP2C9, CYP2C19, and CYP2D6 are well-recognized for their polymorphisms in drug metabolism with differences observed among individuals of the same ethnic group, as well as across various ethnic backgrounds3,4,5,6.

Figure 1:
The percentage of Phase I and II metabolism that each enzyme contributes correlates with the estimated relative size of the corresponding pie chart7.

[From Evans and Relling (1999). Pharmacogenomics: Translating functional genomics into rational therapeutics. Science, 286, 487-491] *

Cyprotex can screen compounds through different genetic variants of drug metabolizing enzymes to understand the impact of genetic polymorphisms on drug metabolism.

 

Reaction Phenotyping

In order to determine which cytochrome P450 enzymes are involved in the metabolism of a compound, reaction phenotyping studies are recommended in early development. This information is useful for predicting possible drug-drug interactions with co-administered therapies, and in identifying whether polymorphic enzymes play a significant role in the drug metabolism.

Available gADME™ reaction phenotyping services include:

  • Phase I:
    • Cytochrome P450 enzymes (CYP)
    • Flavin monooxygenases (FMO)
    • Monoamine oxidases (MAO)
    • Carboxylesterases (CES)
    • Aldehyde oxidases (AOX)
    • Aldehyde dehydrogenases (ALDH)
    • Aldo-keto reductases (AKR)
    • Alcohol dehydrogenases (ADH)
    • Hydroxysteroid dehydrogenases (HSD)
  • Phase II:
    • UDP-glucuronyltransferases (UGT)
    • Sulfotransferases (SULT)
    • N-Acetyltransferases (NAT)
    • Glutathione S-transferases (GST)

gADME™ expands the offering of Cyprotex’s existing drug metabolism assays:

  • Metabolic stability (microsomes, hepatocytes, S9, plasma)
  • Reversible CYP450 Inhibition
  • CYP450 Time Dependent Inhibition
  • CYP450 Induction
  • CYP450 Reaction Phenotyping
  • UGT Inhibition
  • MAO Inhibition
  • Metabolite Profiling

Contact us to learn more about how Cyprotex’s gADME™ can help your drug development efforts.

References

1 Nebert DW et al. (1996) DNA Cell Biol 15; 273-280
2 Aspinall MG and Hamermesh RG (2007) HBR October: 1-9
3 Abass K et al. (2010) Fungicides 22; 441-468
4 Božina N et al. (2009) Arh Hig Rada Toksikol 60; 217-242
5 Guengerich FP et al. (2006) AAPS Journal 8; E101-E111
6 Ingelman-Sundberg M et al. (2007) Pharmacol Ther 116; 496-526
7 Evans WE and Relling MV (1999) Science 286; 487-491

* Reprinted with permission from AAA. Readers may view, browse, and/or download material for temporary copying purposes only, provided these uses are for noncommercial personal purposes. Except as provided by law, this material may not be further reproduced, distributed, transmitted, modified, adapted, performed, displayed, published, or sold in whole or in part, without prior written permission from the publisher.

 

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This website was last updated
on 22nd April 2014
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