This system represents a fully integrated approach to high throughput ADME evaluation in support of drug discovery. Cytochrome P450 inhibition is measured for both CYP3A4 and CYP2D6 isozymes. The CYP inhibition method combines both liquid handlers and an integrated fluorescence plate reader to perform single concentration percent inhibition assays for 88 compounds. The incubation plates are transferred off-line for final semi-quantitative analysis using high throughput parallel LC/MS. The HLM stability assay utilizes a Multimek 96-channel pipettor for liquid handling. The SAGIAN core robotics system integrates devices such as liquid handlers, plate hotels and incubators through the use of an ORCA robotic arm. This automated solution has led to an increase in capacity, throughput and reliability for both in vitro assays. In response to the throughput demands of parallel synthesis, we have incorporated a SAGIAN core robotics system for the determination of both metabolic stability in human liver microsomes (HLMs) and cytochrome P450 (CYP450) inhibition. Our laboratory has implemented high throughput in vitro absorption, distribution, metabolism and excretion (ADME) assays which address absorption, metabolism, and physico-chemical properties in an effort to identify potential development liabilities early, thereby minimizing discovery to market attrition.
Early determinations of pharmaceutical properties can serve as predictors of a compound's likely development success.
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