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The use of the plasma epinephrine (EPI) level as an index of adrenomedullary activity in humans is complicated by the rapid removal of EPI from plasma by many tissues. To determine whether the kinetics of distribution and metabolism of EPI could be best quantified using the isotope dilution method or a mathematical modeling technique, eight human subjects received a [3H]EPI infusion for 50-60 min. Analysis of the steady state arterialized plasma levels of EPI and [3H]EPI using the isotope dilution technique showed that the basal plasma EPI appearance rate is 0.87 +/- 0.11 nmol/m2.min, and the basal plasma EPI clearance rate is 1.63 +/- 0.14 L/min.m2. Mathematical modeling of the [3H]EPI levels revealed that a biexponential curve fit was superior to monoexponential and triexponential curve fits. A two-compartment model was the minimal compartment model that accurately described EPI kinetics. The basal plasma EPI appearance (0.82 +/- 0.16 nmol/m2.min) and EPI clearance (1.67 +/- 0.15 L/min.m2) rates that were estimated from this two-compartment model are similar to the results derived from the isotope dilution method. Mathematical modeling revealed a large extravascular mass of EPI. We conclude that the isotope dilution and mathematical modeling techniques similarly describe plasma EPI kinetics in humans. Kinetic analysis using mathematical modeling provides new insights into adrenomedullary function in humans.

There is an age-related increase in plasma norepinephrine (NE) in humans that is due to both an increase in NE appearance into plasma and a decrease in plasma NE clearance. However, previous studies demonstrated no difference in plasma epinephrine (EPI) in young and old subjects, and the effect of aging on plasma EPI appearance and clearance is unclear. To study age differences in basal NE and EPI metabolism we infused eight young (aged 19-26 yr) and eight old (aged 64-74 yr) normal subjects with [3H]NE or [3H]EPI (15 microCi/m2 bolus dose plus 0.35 microCi/m2/min for 50 min) to achieve steady state conditions on separate days. The old subjects had higher arterialized plasma NE levels [mean, 217 +/- 13 (+/- SE) vs. 149 +/- 12 pg/mL; P less than 0.005] and plasma NE appearance. In contrast, neither plasma EPI levels (98 +/- 8 vs. 104 +/- 10 pg/mL; P = NS) nor EPI appearance rates were different in the old and young subjects. The plasma clearance rates of EPI and NE were nearly identical in the young subjects (1.63 +/- 0.14 vs. 166 +/- 0.09 L/min X m2; P = NS). Plasma NE clearance was lower in the old compared to the young subjects (1.38 +/- 0.06 vs. 1.64 +/- 0.10 L/min X m2; P less than 0.05) and was lower than EPI plasma clearance in the same subjects. Although NE and EPI can be removed by both neuronal and nonneuronal uptake mechanisms, and mean plasma clearance values for NE and EPI are the same in the young, the age-related decline in catecholamine clearance is specific for NE. This finding implies a differential effect of age on a catecholamine removal mechanism that is specific for NE.