title: Bioanalytical strategies to support a discovery research programme.
abstract: To facilitate the selection of drug candidates from a discovery research programme, a strategy was developed to assess the preliminary metabolism and pharmacokinetics of numerous chemical entities. A three-level "screening funnel" was set up, using both in-vitro and in-vivo techniques, requiring bioanalytical methods for the determination of parent compound. Simple high performance liquid chromatography (HPLC)/UV assays with minimal sample workup were adequate for the initial high throughput in-vitro screen used to assess in-vitro metabolic stability but a more selective sample extraction method was required for the second level of the screen. Here, rats were infused with drug to steady-state concentrations and whole blood, plasma, and brain tissue homogenate were analysed to assess clearance and to investigate blood/brain barrier penetration. Generally, HPLC/UV was adequate as only moderate sensitivities were required. However, the final level of the screen, a rat PO/IV bioavailability study, needed far more sensitive assays and often presented significant analytical challenges.
authors.affiliation: Upjohn Laboratories--Europe, Crawley, West Sussex, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Rees
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D051381:Rats; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics; D013056:Spectrophotometry, Ultraviolet
chemical_list: D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin