2006High throughput microsomal stability assay for insoluble compounds书籍.pdf

International Journal of Pharmaceutics 317 (2006) 54–60 High throughput microsomal stability assay for insoluble compounds Li Di ∗, Edward H. Kerns, Susan Q. Li, Susan L. Petusky Wyeth Research, P.O. Box CN 8000, Princeton, NJ 08543-8000, United States Received 15 January 2006; received in revised form 3 March 2006; accepted 3 March 2006 Available online 17 March 2006 Abstract High throughput metabolic stability assays are widely implemented in drug discovery to guide structural modification, predict in vivo performance, develop structure-metabolic stability relationships, and triage compounds for in vivo animal studies. However, these methods are often developed and validated using commercial drugs. Many drug discovery compounds differ from commercial drugs, with many having high lipophilicity, high molecular weight and low solubility. The impact of very low solubility on metabolic stability assay results was explored. Two metabolic stability assays, the ‘aqueous dilution method’ and the ‘cosolvent method, were compared. For commercial drugs and most discovery compounds having reasonable drug-like properties, the two methods gave comparable results. For highly lipophilic, insoluble drug discovery compounds, the ‘aqueous dilution method’ gave artificially higher stability results. The cosolvent method performs compound dilutions in solutions with higher organic solvent content and adds solutions directly to microsomes to assist with solubilization, minimize precipitation and reduce non-specific binding to plastics. This method is more applicable in drug discovery where compounds of a wide range of solubility are studied. © 2006 Published by Elsevie