High-throughput stability

Kerns, E.H. Di, L. Kleintop, T. Zhang, M. Petusky, S. McConnell, O. High Throughput Stability Profiling for Drug Discovery, in Presented at the Symposium on Chemical and Pharmaceutical Structure Analysis, September, 2000. 

With this focus on CYP and fiver metabolism, most companies have established high throughput assays to measure compound stability in the presence of human (or preclinical species) fiver microsomes [49]. Disappearance of starting compound from an incubation with microsomes is monitored. Measurement at a single time point enables a rank-ordering of compounds for stability based on percent of parent compound remaining acquisition of data at multiple time points allows determination of half-life, intrinsic clearance, and extrapolation to a predicted in vivo clearance [50]. 

Aucamp, J.P., Cosme, A.M., Lye, G.J. andDalby, P.A. (2005) High-throughput measurement of protein stability in microtiter plates. Biotechnology and Bioengineering, 89, 599-607. 

However, several articles in the area of microwave-assisted parallel synthesis have described irradiation of 96-well filter-bottom polypropylene plates in conventional household microwave ovens for high-throughput synthesis [16-19]. While some authors have not reported any difficulties associated with the use of such equipment [19], others have experienced problems in connection with the thermal instability of the polypropylene material itself [17] and with respect to the creation of temperature gradients between individual wells upon microwave heating [17, 18]. While Teflon (or similar materials such as PFA) can eliminate the problem of thermal stability, the issue of bottom-filtration reaction vessels has not yet been adequately addressed. 

Another approach to increase HPLC speed is the use of higher temperatures. The viscosity of a typical mobile phase used in reversed-phase separation decreases as the column temperature is increased. This allows an HPLC system to operate at a higher flow rate without suffering too much from increased back pressure. Zirconia-based packing materials provide excellent physical and chemical stability. They have been used successfully for high-throughput bioanalysis at elevated temperatures.9... 

Jenkins, K.M. et al. 2004. Automated high throughput ADME assays for metabolic stability and cytochrome P450 inhibition profiling of combinatorial libraries. J. Pharm. Biomed. Anal. 34 989. 

Xu, R. et al. 2002. Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries. J. Am. Soc. Mass Spectrom. 13 155. 

TDM has improved the performance of anticancer, antidementia, antidepressant, antiepileptic, anticonvulsant, antifungal, antimicrobial, antipsychotic, antiretroviral, anxiolytic, hypnotic, cardiac, addiction treatment, immunosuppressant, and mood stabilizer drags for more than 30 years.2-9 Many analytical procedures evolved as analytical techniques and instrumentation have advanced. This chapter briefly reviews the different types of analytical methods the applications of high-throughput techniques in TDM are discussed in detail. 

---