Extrahepatic Metabolism may Complicate the IVIVC in Rats
As the liver is generally considered the organ most involved in metabolic transformations,
metabolism in other organs is often overlooked and in vitro screening systems largely adopted in drug
discovery are generally based on liver tissue fractions.
First pharmacokinetics of new chemical entities (NCEs) are initially based on preclinical species; rat is used
in the majority of the cases to assess early in vitro-in vivo correlation (IVIVC). It is important, in this
perspective, to address as early as possible the relevant differences between rat and human and the limits
using pharmacokinetic studies in this species as a model for the human PK.
In this paper the author reports at least three clear examples in drug discovery where the use of hepatic in-vitro systems
resulted in a very poor IVIVC due to relevant extrahepatic metabolism in rats.
Keywords: CYP1A1, extrahepatic metabolism, extrahepatic microsomes, human pharmacokinetic prediction, in vitro - in vivo
correlation, liver microsomes, lung metabolism, lung microsomes, preclinical animal model, recombinant CYP450.
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