Hemodynamic influences upon the variance of disposition residence time distribution of drugs

Abstract

A recirculation model of drug disposition is used to interpret the physiological meaning of the variance of residence time distribution (VDRT). The pharmacokinetic parameter VDRT is determined by the means and variances of the transfer times across the organs, as well as by the respective blood flow and extraction ratios. The model is illustrated for a specified distribution of organ transit times assuming flow limited mass transport. Based on data from the literature, the influence of changes in cardiac output and its regional distribution on the variance of recirculation and residence times, respectively, is predicted for lidocaine. Thereby the study is focused on the effect of certain cardiovascular states (shock, hypoxia, exercise, sympathomimetic drugs). Unlike pharmacokinetic parameters derived from the zeroth and first curve moments, the relative residence time dispersion is found to be affected by a redistribution of the blood flow among the noneliminating organs. The equations presented allow a simple and rapid calculation of clinically relevant pharmacokinetic parameters from physiological and physicochemical data.