A software tool for patient stratification by genetic variations in drug metabolism

人类药物代谢和清除由肝酶驱动，最值得注意的是细胞色素P450（或CYP）。CYP是一个非常重要的酶超家族，在药物发现和开发中具有重要意义。由于CYP酶的高度多态性，特别是CYP 2D6，与目前处方药物相关的差异代谢和不良事件在历史上没有得到很好的理解。CYP2D6是一种重要的酶，参与超过25%的临床药物的代谢，其中许多药物被大量使用，占英国处方的80%左右。它是高度受多态性，导致显着的临床后果。CYP2D6目前处于个性化医疗研究的最前沿，因为它具有高水平的遗传变异，以及药物代谢不良对患者健康的影响。生物信息学领域的进展使得有可能产生CYP2D6变体的结构模型，这些变体从实验室工作中已知，以证明不同的反应速率，即超快速、广泛、中间和弱代谢者。该项目旨在开发一种临床软件工具，该工具能够根据个体CYP2D6活性对患者进行分层，该分层基于对处方药物反应的临床观察，这些药物可独立使用或与基因型信息结合使用。

Human drug metabolism and clearance is driven by liver enzymes, most notably the Cytochrome P450s (or CYPs). CYPs are a well characterised superfamily of enzymes, which are of great importance in drug discovery and development. Historically not so well understood is the differential metabolism and adverse events associated with currently prescribed drugs due to the highly polymorphic nature of CYP enzymes, in particular CYP2D6. CYP2D6 is an important enzyme involved in the metabolism of over 25% of clinical drugs, many of these heavily used and collectively making up around 80% of UK prescriptions. It is highly subject to polymorphisms which cause significant clinical consequences. CYP2D6 is currently at the forefront of research for personalised medicine due to its high level of genetic variation and the effects that poor drug metabolism can have on a patient’s health. Advances in the field of bioinformatics have made it possible to produce structural models of CYP2D6 variants that are known from laboratory work to demonstrate different reactive rates, being ultra-rapid, extensive, intermediate and poor metabolisers. This project seeks to develop a clinical software tool that enables the stratification of patients according to individual CYP2D6 activity based on clinical observations of their response to prescribed drugs that may be used independently of, or in conjunction with, genotypic information.