samedan logo
 
 
 
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

SONOTECŪ launches industrial clamp-on flow meter for plastic tubes and pipes for the use in hazardous areas of Zone 1 according to ATEX/IECEx

The new SEMIFLOW Ex1 Set opens a new product category of intrinsically safe ultrasonic flow sensors with control gear for non-contact liquid flow measurement on small and midsize rigid plastic tubes to ensure safe operation in hazardous areas. SEMIFLOW CO.66 PI Ex1 sensors are protected against explosion hazard by gases, vapors, and liquids according to the gas group IIB. The device protection level (EPL) is "Gb" for the use in Zone 1 according to ATEX/IECEx.
More info >>

White Papers

Modifying MDI Canister Surfaces to Improve Drug Stability & Drug Delivery

Presspart Manufacturing Ltd

Hydrofluoroalkane (HFA)-based propellants are widely used in modern metered-dose inhalers (MDIs), due to their lack hazardous and environmentally-damaging effects. However, an HFA's active pharmaceutical ingredient can interact with the canister substrate, causing deposition of the drug to the canister walls, or interact with the solution, causing degradation and resulting in increased impurity levels. Over the past few years, a number of surface coatings have been developed that can be applied to MDI canisters and valve components, to protect the contents from deposition and degradation. More recently, plasma processes have been developed to modify and improve the surface energy performance of a MDI canister. This approach has a number of advantages to alternative coatings but requires careful optimisation to ensure the highest quality finish and MDI performance. Richard Turner, Business Development Director, Presspart Manufacturing Ltd, explains.
More info >>

 
Industry Events

World Vaccine Congress Europe

18-21 October 2020, Barcelona, Spain

The World Vaccine Congress is an award-winning series of conferences and exhibitions that have grown to become the largest and most established vaccine meeting of its kind across the globe. Our credibility is show through the prestigious scientific advisory board that spend months of hard work creating a new and topical agenda, year on year.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement