spacer
home > ebr > autumn 2017 > driving discovery
PUBLICATIONS
European Biopharmaceutical Review

Driving Discovery

Cytochromes P450 (P450s) are a superfamily of enzymes present in all organisms. They contain a haem moiety that forms the catalytic centre and primarily function as monooxygenases, adding an oxygen to their substrates (see Figure 1) (1). P450s are highly relevant in drug discovery because they are responsible for Phase 1 metabolism of approximately 70-80% of drugs (2). Several P450 isoforms contribute to human drug metabolism; the most important of these are summarised in Figure 2. Many issues affecting potential drugs can arise from P450 metabolism:

  • Rapid metabolism can lead to poor bioavailability or rapid clearance, resulting in low exposure and efficacy
  • Co-administration of drugs can cause drug-drug interactions (DDIs), whereby inhibition or induction of a P450 isoform by one therapeutic can dramatically affect the metabolism of another, causing significant changes in exposure
  • Genetic polymorphisms in patient populations affect the rates of metabolism by major P450 isoforms, including CYP2D6 and CYP2C19, generating large variabilities in exposure between patients
  • Metabolism by P450s can lead to bioactivation of compounds and the formation of reactive or toxic metabolites

In an effort to reduce these issues, in vitro assays of P450 metabolism-related properties are widely used in the drug discovery process (3). High-throughput assays, such as measurement of turnover in human liver microsomes or inhibition of P450 isoforms, are applied as early screens. However, more detailed studies, such as metabolite identification, remain expensive and time-consuming, hence they are typically applied later in the process to a limited number of compounds.

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
Matthew Segall has an MSc in computation from the University of Oxford, UK, and a PhD in theoretical physics from the University of Cambridge, UK. At Camitro, ArQule and Inpharmatica, he led a team developing predictive absorption, distribution, metabolism and excretion (ADME) models and intuitive decision-support tools for drug discovery. In 2006, Matt became responsible for management of Inpharmatica's ADME business and, following acquisition of Inpharmatica, he took up the role of Senior Director of BioFocus DPI's ADMET division. In 2009, he led a management buyout of the StarDrop business to found Optibrium Ltd, which develops software for small molecule design, optimisation and data analysis.
spacer
Matthew Segall
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

BioIVT to Host Webinar Describing In Vitro Models to Predict Herb-Drug Interactions

BioIVT, a leading provider of biospecimens and related services, today announced that it will be hosting a webinar entitled “Whole-cell In Vitro Models Can Predict Clinically-relevant Herb-Drug Interactions (HDIs)” at 11 am ET on June 20.
More info >>

White Papers

The Use of Stainless Steel Equipment Within Laboratories and Clean Rooms

Teknomek Ltd

Teknomek explains why stainless steel is the material of choice for laboratories and hygienic manufacturing.
More info >>

 
Industry Events

On Helix 2018

10-11 July 2018, The Cambridge Building, Babraham Research Campus

ON Helix is a two-day event aimed at informing delegates of how to turn early stage inventions and ideas into innovative health treatments (new medicines, novel biomarkers, useful medical devices or improved medical practices).
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement