Improved method for single-bolus kinetic measurements using a noncleared reference indicator

After intravenous injection of a tracer as a single bolus, its concentration decreases as it mixes with the plasma, disperses throughout the circulation, and enters body pools. Kinetic values that are dependent on early concentrations may be in considerable error because mixing is not instantaneous throughout the circulation, and this problem is particularly acute in the mammalian fetus, with its distinctive circulatory pattern. To minimize this error, a method was developed in which the noncleared reference tracer 125I-labeled albumin was injected together with a representative, rapidly cleared metabolite 14C-labeled palmitic acid, and the former was used to correct for mixing delay. A total of 19 disappearance curves were studied after intravenous injection into seven near-term fetal sheep. Kinetic values were calculated with and without correction for mixing delay. Taking account of mixing delay increased the calculated volume of distribution 41% [from 44 +/- 4 (SE) to 62 +/- 3 ml/kg, P < 0.001], increased plasma clearance rate 13% (from 41 +/- 2 to 47 +/- 1 ml-min-1.kg-1, P < 0.002), decreased the rate constant for irreversible loss 26% (from 1.05 +/- 0.07 to 0.78 +/- 0.04 min-1, P < 0.001), and increased the calculated effective half-life 26% (0.71 +/- 0.06 to 0.90 +/- 0.05 min, P < 0.001). Thus use of the additional reference marker significantly altered calculated results and provided values believed to more accurately describe rapid disappearance from the central mixing compartment into metabolic pools.