Drug distribution. The forgotten relative in clinical pharmacokinetics

The target concentration strategy has proved a valuable approach for dose individualisation, giving proper weight to the high interindividual variation in plasma concentrations. Nevertheless, optimisation of plasma concentrations does not necessarily yield optimal pharmacodynamic effects because variability in the plasma concentration-effect relationship is far from insignificant. We argue that this is due not only to unpredictable target tissue sensitivity but also to a highly variable, and equally unpredictable, distribution process from plasma into the interstitial space of the target tissue, the true effect compartment. This is borne out by recent results from studies employing modern techniques that enable direct measurement of target tissue drug concentrations, like magnetic resonance spectroscopy, single photon emission computed tomography, and tissue microdialysis. Such forthcoming results highlight the importance of the distribution process as a key factor determining drug response. Clinical pharmacology should seek an improved understanding of the biological determinants governing not only plasma but tissue drug concentrations.