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Polymorphic and Non-CYP mediated metabolism

Non-CYP mediated metabolism

  • Approximately one third of the top 200 prescribed drugs which undergo drug metabolism are substrates for metabolic clearance mediated by enzymes other than CYPs. The most prevalent are UDP-glucuronosyl transferases and esterases accounting for approximately 8% and 5% of the metabolised drugs respectively1,2.
  • Numerous other more minor pathways exist including: flavin monooxygenases (FMO), monoamine oxidases (MAO), aldehyde oxidases (AOX), aldehyde dehydrogenases (ALDH), aldo-keto reductases (AKR), alcohol dehydrogenases (ADH) and hydroxysteroid dehydrogenases (HSD), sulphotransferases (SULT), N-acetyltransferases (NAT) and glutathione S-transferases (GST).
  • Both the EMA3 and draft FDA4 guidance on drug interactions suggest that both CYP and non-CYP pathways should be elucidated if thought to contribute a significant amount to drug elimination.
  • Cyprotex’s non-CYP metabolism service enables a greater understanding of which non-CYP enzymes might be involved in the metabolism of your compounds, or if your compounds are inhibitors of non-CYP enzymes. These data can be used to determine potential drug-drug interactions. 

Reaction Phenotyping

In order to determine which CYP and non-CYP 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 reaction phenotyping services include:

  • Phase II:
    • UDP-glucuronyltransferases (UGT)
    • Sulphotransferases (SULT)
    • N-Acetyltransferases (NAT)
    • Glutathione S-transferases (GST)

Enzyme Inhibition Studies

Understanding whether a compound can inhibit drug metabolising enzymes is important in establishing its drug interaction potential. Also, in some circumstances inhibition of an enzyme may be a critical mechanism of action for a drug (e.g., monoamine oxidase inhibitors in the treatment of Parkinson’s disease).

Available enzyme inhibition services include:

  • Phase II:
    • UDP-glucuronyltransferases (UGT)
    • Sulphotransferases (SULT)
    • N-Acetyltransferases (NAT)
    • Glutathione S-transferases (GST)

Genetic Polymorphisms

To date, over 30 DMEs are known to be implicated in drug metabolism and many of these enzymes are polymorphic5. 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 ADRs6. Specifically, the cytochrome P450 enzymes, such as CYP2C9, CYP2C19, and CYP2D6 are well-recognised for their polymorphisms in drug metabolism with differences observed among individuals of the same ethnic group, as well as across various ethnic backgrounds7,8,9.

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, 487-49110] *

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

The services described above expand the offering of Cyprotex’s existing drug metabolism assays:

References

1 Williams JA, et al., (2004) Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCI/AUC) ratios. DMD 32; 1201-1208
2 Beaumont K et al., (2010) ADMET for the medicinal chemist. In RCS Drug Discovery Series No. 1: Metabolism, Pharmacokinetics, and Toxicity of Functional Groups: Impact of Chemical Building Blocks on ADMET. Edited by Smith DA; 61-98
3 The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions (Adopted 2012)
4 Draft FDA Guidance for Industry – Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, Feb 2012
5 Nebert DW et al. (1996) Human drug metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol 15; 273-280
6 Aspinall MG and Hamermesh RG (2007) Realizing the promise of personalized medicine. Harvard Business Review October: 109-117
7 Božina N et al. (2009) Genetic polymorphisms of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. Arh Hig Rada Toksikol 60; 217-242
8 Guengerich FP et al. (2006) Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS Journal 8; E101-E111
9 Ingelman-Sundberg M et al. (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116; 496-526
10 Evans WE and Relling MV (1999) Pharmacogenomics: Translating functional genomics into rational therapeutics. 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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