Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding I. Theoretical considerations

Abstract

We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, f_p) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both V_β and the model-independent V_SS) were inaccurate/invalid; b) V _β based on unbound drug was misleading; c) the model-independent V_SS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms ( $\bar f_P $ and $\bar V_{SS}^T $ ) were introduced which provide additional insight concerning the disposition of this type of drug. The $\bar f_P $ is the area-weighted average fraction unbound in the plasma and $\bar V_{SS}^T $ is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.