Further thoughts about distributions.....

For the most part, the volume of distribution Vd is conceptualized as little more than a proportioning factor between the administered dose of a drug and the initial plasma concentrations. While it was important in determining the C0, it had little impact on drug exposure, the AUC or steady state concentrations. These were squarely in the domain of clearance mechanisms.

We expected that while protein binding was inversely related to the Vd, the free drug concentrations would eventually equilibrate across all tissue compartments, regardless of tissue binding. What was observed in the plasma of the central compartment would represent what was happening in all tissues. Furthermore if free drug clearance remained unchanged, free concentrations would remain unchanged, regardless of protein or tissue binding.

According to these ideas, central compartment pharmacokinetics was of prime importance in understanding drug efficacy, or lack of it.

In recent years, the increasing appreciation that few molecules actually permeate across membranes with the involvement of transporter processes, have led many to question the wisdom of an approach that assumed drug molecules existed in equilibrium across membranes and consequently, tissue compartments. Depending on the expression and function of transporters at various membranes, drug concentrations can vary independently of central compartment concentrations. Hence, in some individuals, the plasma concentrations may mirror concentrations in any tissue compartments if the transporters involved are ubiquitous.

Conversely, in some individuals, the concentrations in tissues 'compartments' may be very different if specific transporters are differentially expressed, leading to widely different efficacy-toxicity profiles even though central compartment concentrations appear invariate.