In order to investigate the metabolism of apo A-IV within TRL and plasma, we assessed TRL and plasma apo A-IV kinetics in 19 and 4 subjects, respectively, consuming an average US diet for a 6-week period. At the end of this diet study, each subject received a primed-constant infusion of deuterated leucine over a 15 h time period with hourly feeding, and blood samples were drawn at 10 time points. TRL was separated by ultracentrifugation. Apo A-IV was isolated by immunoprecipitation and/or SDS-PAGE. Apo A-IV concentrations were determined by immunoelectrophoresis. Stable isotope tracer/tracee ratios were measured by gas chromatography/mass spectrometry, and the data were analyzed by multicompartmental modeling. The mean concentrations of plasma and TRL apo A-IV during the isotope infusion period were 21.0+/-3.2 and 0.66+/-0.25 mg/dl, respectively, and these values were 11.5 and 30.5% higher than those of fasting samples. The mean TRL and plasma apo A-IV residence times (RT) were 1.97+/-0.57 and 2.71+/-0.65 days, and transport rates (TR) were 0.17+/-0.19 and 3.90+/-1.24 mg/kg per day, respectively. There were significant correlations between TRL apo A-IV concentrations and TR (r(2)=0.79, P<0.001), and between TRL apo A-IV pool size and TRL cholesterol levels (r(2)=0.29, P=0.02). Our data indicated that; (1) TRL apo A-IV has a RT of 1.97 days which is similar to that earlier reported for HDL apo A-IV; (2) Apo A-IV recirculates between TRL and other slowly turning over pools; (3) the primary determinant of TRL apo A-IV levels is its TR; and (4) there is no correlation between TRL apo A-IV and apo B48 fractional catabolism in TRL.