title: High throughput microsomal stability assay for insoluble compounds.
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.
authors.affiliation: Wyeth Research, P.O. Box CN 8000, Princeton, NJ 08543-8000, USA. DIL@WYETH.COM
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.forename: Edward H
authors.initials: EH
authors.lastname: Kerns
authors.forename: Susan Q
authors.initials: SQ
authors.lastname: Li
authors.forename: Susan L
authors.initials: SL
authors.lastname: Petusky
mesh_terms: D000097:Acetonitriles / Q000737:chemistry; D000818:Animals; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D000097:Acetonitriles; D004364:Pharmaceutical Preparations; D004121:Dimethyl Sulfoxide; C032159:acetonitrile