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Comb Chem High Throughput Screen. 2010 Feb;13(2):159-69.

Scaling in vivo pharmacokinetics from in vitro metabolic stability data in drug discovery.

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Theravance Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA.


In this review, the current approach to predicting hepatic clearance from in vitro metabolic systems is discussed along with a survey of current industry practice. The definitive method of determining intrinsic clearance remains the measurement of Michaelis-Menten parameters derived from metabolite formation rate data. However, in drug discovery this method has limitations which result in the method most commonly applied being the half-life method utilizing a single, low substrate concentration. Additionally, the importance of correcting in vitro intrinsic clearance values for futile binding within the incubation has become accepted, although the majority of the respondents to the industry survey do not currently correct for this. It is also apparent that most investigators employ standard incubation conditions for determining intrinsic clearance which may not be appropriate for all compounds. Adapting these conditions to vary both the substrate and enzyme concentrations offers a relatively simple method to gain useful information regarding potential Km values and in vitro futile binding. Although there are many factors that influence the relationship between intrinsic clearance and hepatic clearance, even in a discovery setting opportunities exist for limited tailoring of assay conditions, which when combined with some judicious assumptions and forethought, make it possible to use intrinsic clearance values in a rational manner to identify compounds with the desired pharmacokinetic properties.

[Indexed for MEDLINE]

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