RECIRCULATORY PHARMACOKINETIC MODELS OF MARKERS OF BLOOD, EXTRACELLULAR FLUID AND TOTAL-BODY WATER ADMINISTERED CONCOMITANTLY

Pharmacokinetic models were developed to describe the disposition of m arkers of extracellular fluid (inulin) and total body water (antipyrin e) from the moment of injection to incorporate the intravascularlar mi xing component, determined by a marker of intravascular space (indocya nine green, ICG). The simultaneous dispositions of these markers were characterized in four halothane-anesthetized dogs, after injection of ICG, [C-14]-inulin, and antipyrine into the right atrium, femoral arte rial blood samples were collected every 3 sec for 1 min and less frequ ently to 20 min for ICG and to 360 min for inulin and antipyrine. ICG and antipyrine concentrations were measured by high-performance liquid chromatography and [C-14]-inulin concentrations were measured by liqu id scintillation counting. The marker concentration histories were cha racterized completely by fully identifiable recirculatory compartmenta l models. Because neither ICG nor inulin distribute beyond intravascul ar space before recirculation, their first-pass data were modelled sim ultaneously to improve confidence in central circulation model paramet ers. This central circulation model included an estimate of cardiac ou tput that was retained in the recirculatory models of all markers. Thr ee tissue compartments were identified for antipyrine, a lipid soluble marker that equilibrates with tissue (including the lung) and estimat es total body water and tissue blood flow. The hydrophilic marker, inu lin, diffuses into interstitial fluid so slowly that only two extravas cular compartments were identified. These models may be used to determ ine how cardiac output and its distribution, pulmonary drug uptake, an d nondistributive blood flow contribute to variability in patient resp onse to drugs with a rapid onset of effect.