The influence of cardiac output distribution on the tissue/plasma drug concentration ratio

In pharmacokinetics, it is currently assumed that blood and interstitial spaces belong to the central compartment, when the solute is quickly equilibrated between both fluids. Taking into account that the same extracellular fluid dissolves the drug either in the plasma or in the interstitium, both drug concentrations (intra and intravascular) should be identical. However, this equality may not exist when there is a dissimilar distribution of blood flow among the organs. A closed, two-zone, three-compartment model was mathematically investigated. Compartment 1 was intravascular, and compartments 2 and 3 were extravascular. The fluid within the compartment 1 was supposed to be pushed by a pump, and to be distributed towards two different zones. One of these zones was in contact with the compartment 2, and the other with compartment 3. The drug could be exchanged between the compartments 1 and 2 or 1 and 3, by mean of first-order kinetics (k12, k21, k13, k31). It was assumed a very fast flow that assured instantaneous homogeinity of drug concentration in compartment 1. Pressure was kept constant, so an increase in the pump output distribution towards one zone is compensated by a decrease towards the other zone. At time infinite the drug concentration (C) ratio between compartments yielded: C2/C1 = k12.sigma.V1/(k21.V2) and C3/C1 = k13.(1-sigma).V1/(k31.V3), being sigma: the pump output fraction served to the zone where compartment 2 was located, and Vi: the volumes of compartments. So, at the equilibrium the concentrations are not necessarily identical between the extravascular and intravascular sites. In conclusion, as the cardiac output distribution changes due to circadian rythms and cardiovascular active drug administration, current therapeutic drug monitoring and bioequivalence studies using plasma as biologic fluid would be controversial issues.