In vivo pharmacokinetic screening

The determination of the concentration of a drug in plasma is an accepted surrogate marker for drug exposure. The use of LC-MS-based approaches for the quantitative analysis of a drug or its metabolite in a physiological sample such as plasma or serum is perhaps the hallmark of PK studies in drug discovery. The PK profiles derived from LC-MS data provide bioavailability and half-life information for drug candidates. These PK profiles are used to directly compare lead compounds and select specific compounds for further study. 

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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. 

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. 

Beaudry, R LeBlanc, J.C.Y. Coutu, M. Brown, N.K. In Vivo Pharmacokinetic Screening in Cassette Dosing Experiments The Use of On-Line Prospekt Liquid Chromatography-Atmospheric Pressure Chemical Ionization Tandem Mass Spectrometry Technology in Drug Discovery, Rapid Commun. Mass Spectrom. 12(17), 1216-1222 (1998). 

Cerep evaluates hits, leads, and new compounds from the metabolic point of view using liver microsomes and recombinant cytochrome P450s (275). The results of these metabolic screening studies offer insight to the rate of metabolic pathways, in vivo pharmacokinetic properties, and drug-drug interactions. 

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. 

Klopf W, Worboys P. Scaling in vivo pharmacokinetics from in vitro metabolic stability data in drug discovery. Comb Chem High Throughput Screen. 2010 13(2) 159—69. 

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