Influence of Sampling Site and Fluid Flow on the Accuracy of Total Body Clearance Calculation

Abstract

Studies have showed that by assuming arteriovenous drug concentrations are homogenous after intravenous injection, the determination of total body clearance based on venous drug concentrations is often inaccurate. This study considers the use of a fluidic pharmacokinetic profile generator where 28 different profile types were generated corresponding to a physiological model with varying sampling sites, administration locations, and fluid flow rates. Clearance was calculated using established equations, commercial software, and recently proposed models. The results show large differences in clearance values calculated with published equations and commercial software relative to the actual value of clearance. Alterations in sampling site, administration location, and fluid flow rates each influence the extent of calculation errors. The data show that a significant drug concentration gradient exists within the central circulatory system. The results show that the best way to address this issue would be to inject the drug at a peripheral location to allow for sufficient mixing and then sample from a large vein. Extrapolating for missing data can also lead to large errors in clearance calculation; this can be addressed by collecting more samples early after IV bolus administration or by collecting data during steady state conditions for an IV infusion.

Keywords: blood flow; clearance; elimination; in vitro model; nonlinear regression; pharmacokinetics.