Pharmacokinetics screening

Cox, K.A. et al. 1999. Novel procedure for rapid pharmacokinetic screening of discovery compounds in rats. Drug Discov. Today 4 232. 

Beaudry F. et al., 1998. In vivo pharmacokinetic screening in cassette dosing experiments Use of online Pros-pekt liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry technology in drug discovery. Rapid Commun Mass Spectrom 12 1216. 

Wu J. et al., 2000. Direct plasma sample injection in multiple-component LC-MS-MS assays for high-throughput pharmacokinetic screening. Anal Chem 72 61. 

Typically, in this Lrstn vivo pharmacokinetic screening, both intravenous and oral formulations are administered to a rodent species, predominantly rats. If it is possible, the same formulation should be used for both intravenous and oral arms. Although in the discovery phase it is preferable to use low volume, high-concentration cosolvent formulations to increase solubility and hence the amount of drug dosed, it does have increased risks of hemolysis and tissue irritation when administered intravenously. Therefore, cautions need to be taken not to exceed the toxicity levels for the cosolvent. 

Hsieh, Y., and Korfmacher, W. A. (2006). Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening. Curr. Drug Metab. 7 479-489. 

Isocratic focusing effects are used to (1) enhance peak shape (2) allow generic approaches to rapid pharmacokinetic screening, (3) perform online concentration for low level metabolite identification, and (4) provide for reducing the amount of... 

Wu, J. T., Zeng, H., Qian, M., Brogdon, B. L., and Unger, S. E. (2000). Direct plasma sample injection in multiple-component LC-MS-MS assays for high-throughput pharmacokinetic screening. Anal. Chem. 72 61-67. 

Acceptable hits do not need to show ideal behavior, but problem compounds will be removed from consideration. If all the hits fail initial pharmacokinetic screening, several options are possible. First, the search for hits could start over with screening of a new library. Second, the threshold for selection of hits could be lowered to enlarge the pool of hits, some of which may pass the permeability and metabolic screens. Third, the criteria for passing the Caco-2 and microsome screens may be softened to allow some hits to pass.18... 

C. C. 1997. Pharmacokinetic screening for the selection of new drug discovery candidates is greatly enhanced through the use of liquid chromatography-atmospheric pressure ionization tandem mass spectrometry. J. Chromatogr. A, 777,61-66. 

Hop, C. E. Wang, Z. Chen, Q. Kwei, G. 1998. Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening. J. Pharm. Sci., 87, 901-903. 

Huang R, Qian M, Chen S, Lodenquai P, Zeng H, Wu J-T. Effective strategies for the development of specific, sensitive and rapid multiple-component assays for cassette dosing pharmacokinetic screening. Int. J. Mass Spect. 2004 238 131-137. 

Cox, K.A. Dunn-Meynell, K. Korfmacher, W.A. Broske, L. Nomeir, A.A. Lin, C.C. Cayen, M. Barr, W.H. Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats. Drug Discov. Today 1999, 4, 232-237. 

C. Nunes, J. Fenyk-Melody, Effect of signal interference from dosing excipients on pharmacokinetic screening of drug candidates by LC-MS, Anal. Chem., 74 (2002) 6305. 

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