Fig. 1. In a three-compartment pharmacokinetic model, the central or initial volume of distribution (VC) is that volume in which a drug appears to mix instantaneously before distribution throughout the remaining apparent volume of distribution. The ideal VCincludes only the central circulation and nondistributive peripheral pathway(s) of the recirculatory pharmacokinetic model (fig. 2). From VC, drug is distributed to the rapidly (fast) and slowly equilibrating volumes of distribution (VFand VS, respectively) by intercompartmental clearance (ClI). Intercompartmental clearances between VCand both VFand VS(ClFand ClS, respectively) are volume-independent estimates of drug transfer that are determined by blood flow and transcapillary permeability. The volume of distribution at steady state (VSS) is the total volume of distribution and, as such, is the sum of VC, VF, and VS. Elimination clearance (ClE) quantifies the irreversible removal of drug from the body or drug metabolism. CO = cardiac output; ND = nondistributive.