Drug and metabolite concentrations in tissues in relationship to tissue adverse findings: a review

Drug blood (or plasma) levels measured during safety preclinical investigations do not always correlate with toxicological findings. Concentrations in target tissues or, even better, at target receptors would probably be more relevant. In addition, toxicity may be caused by drug metabolites which, in turn, can be tissue specific. Tissue concentrations and tissue metabolism may be crucial for interpreting tissue toxicity.

This paper, starting from the authors' direct experience, focuses on distribution of the parent compound and metabolites in target toxicity tissues and presents a review of several examples where organ or tissue concentrations have been either useful or not relevant for interpreting safety findings. Regulatory aspects and technological progresses are also mentioned.

The authors advocate directing more attention and efforts toward investigating tissue distribution: this approach might reduce late stage attrition. When unexpected tissue toxicity is found, measuring drug concentrations in the target tissue and characterising and measuring tissue metabolites could bring relevant information for interpreting the adverse finding. Evidence of slow accumulation of a long lasting metabolite in a tissue should be considered as an alert: this evidence can be obtained during short-term toxicity studies.