Advancing automation in Compound Management: a novel industrial process underpinning drug discovery.

Faced with ageing infrastructure and ever-increasing demands from hit discovery and lead optimisation functions, AstraZeneca has chosen to develop innovative technologies and process solutions to support the future of drug discovery. These include the miniaturisation of compound storage tubes for high-density storage and rapid access to the corporate collection for feeding samples to the predicted tripling number of high throughput screening (HTS) campaigns. The acoustically- compatible tubes also enable the first fully-acoustic plate production process for faster sample supply to screening with less waste and continued high quality. Operating at a smaller scale reduces compound synthesis, storage, and consumption, prompting miniaturisation of upstream chemistry and downstream biological assays, while offering a transformative and sustainable solution to many drug discovery issues applicable across the industry.

Metabolism of dextrorphan by CYP2D6 in different recombinantly expressed systems and its implications for the in vitro assessment of dextromethorphan metabolism.

Cytochrome P450 2D6 (CYP2D6) mediated formation of dextrorphan (DOR) from dextromethorphan (DEX) is widely used as a marker to assess the activity of this enzyme both in vitro and in vivo. The sequential metabolism of DOR during in vitro studies, particularly using recombinant systems (rCYPs) expressing human CYP2D6, is assumed to be negligible. The extent of metabolism was investigated for a range of DEX and DOR concentrations in microsomal preparations from three different rCYPs expressing human CYP2D6 (yeast, Supersomes and Bactosomes) containing 10 pmol of the enzyme. Bactosomes and Supersomes, but not yeast rCYP microsomes, were capable of metabolising DOR to 3-hydroxymorphinan (HYM). Two novel CYP2D6 related metabolites were identified in Bactosomes, and assigned as single hydroxylations in the phenyl rings of DOR and HYM using ion-trap mass spectrometry. Therefore, in rCYP systems with high turn over rate (e.g. Bactosomes) DOR may not be considered as an end product particularly at low concentrations of DEX; leading to an underestimation of true metabolic rate. The results also put further emphasis on the necessity of optimising study conditions when switching between rCYP sources.