A recirculatory pharmacokinetic model describing the circulatory mixing, tissue distribution and elimination of antipyrine in dogs.

A model of antipyrine disposition from the moment of its injection was developed incorporating the intravascular mixing component as determined by indocyanine green (ICG) kinetics. The simultaneous dispositions of antipyrine and ICG were characterized in five dogs anesthetized with halothane. After injecting antipyrine and ICG into the right atrium, femoral arterial blood samples were collected every 3 sec for the 1st min and less frequently to 20 min for ICG and to 360 min for antipyrine. ICG and antipyrine concentrations were measured by high-performance liquid chromatography and modeled with SAAM 30.1. A fully identifiable recirculatory compartmental model, incorporating the ICG recirculatory model with blood flows and time delays, was used to describe antipyrine disposition. Four distinct antipyrine pharmacokinetic tissue compartments and the distribution clearances assigned to them could be estimated: a pulmonary tissue (0.13 +/- 0.05 I, and 2.51 +/- 0.39 liters/min), a very fast equilibrating tissue (0.12 +/- 0.08 I, and 1.33 +/- 0.22 liters/min), a fast equilibrating tissue (3.21 +/- 0.45 I, and 0.74 +/- 0.09 liters/min) and a slow equilibrating tissue (15.94 +/- 1.8 I, and 0.44 +/- 0.13 liters/min). Although this recirculatory model retains the predominant attributes of traditional pharmacokinetic models, it also can describe completely drug concentrations during the mixing transient when many drugs reach peak effect as well as ascertain the role of cardiac output and its distribution in drug disposition.