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European Biopharmaceutical Review
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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.
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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.
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