Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 93, Issue 2, Pages 364-374Publisher
JOHN WILEY & SONS INC
DOI: 10.1002/jps.10539
Keywords
steady-state volume of distribution; protein and tissue binding kinetics; dissociation rate; mean residence time
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The assumption of an instant equilibrium between bound and unbound drug fractions is commonly applied in pharmacokinetic calculations. The equation for the calculation of the steady-state volume of distribution V-ss from the time curve of drug concentration in plasma after intravenous bolus dose administration, which does not assume an immediate equilibrium and thus incorporates dissociation and association rates of protein and tissue binding, is presented. The equation obtained V-ss = (Dose/ AUC)*MRTu looks like the traditional equation, but instead of mean residence time MRT calculated using the total drug concentration in plasma, it contains mean residence time MRTu calculated using the plasma concentration of the unbound drug. The equation connecting MRTu and MRT is derived. If an immediate equilibrium between bound and unbound drug fractions occurs, MRTu and MRT are the same, but in general, MRTu is always smaller than MRT. For drugs with high protein affinity and slow dissociation rate MRTu may be of an order of several hours smaller than MRT, so that V-ss can be considerably overestimated in the traditional calculation. (C) 2004 Wiley-Liss, Inc.
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