Explanation of the biologically implausible correlation between distribution volume and total body clearance in an open two-compartment model.

The steady-state distribution volume Vss of digoxin decreases with its total body clearance Cltot, which in turn depends on renal function. It is implausible biologically that renal function should influence tissue distribution. The mathematical reason for this discrepancy is the large volume of the central compartment V1 of of 110 l for digoxin obtained by describing the time course of the serum concentrations by an open two-compartment model. With V1 = 17.5 l, Vss is independent of renal function and the regularly observed decrease of V beta with Cltot is explained by the simplification inherent in the one-compartment model used for calculating V beta. A good correlation between kinetic rate constants and biologic data for the exchange of a drug between central and peripheral compartments can be expected only if the volume of the central compartment is close to that of the inulin space. A low volume of the central compartment can be obtained with a multi-compartment model.