[14C]urea and 58Co-EDTA as reference indicators in hepatic multiple indicator dilution studies.

The space distribution and the processes underlying uptake of tracer substrate may be appraised by the multiple indicator dilution technique, after the simultaneous injection of noneliminated vascular (51Cr-labeled red blood cells), extracellular (125I-labeled albumin and [14C]sucrose for high and low molecular weight interstitial space, respectively), and cellular (3H2O) indicators and tracer substrate. When tracer substrates and/or their metabolites containing 14C or 3H labels are being studied, it becomes necessary to find substitutions for the similarly labeled noneliminated indicators. In red blood cell-perfused rat livers, 58Co-EDTA is found to be a good replacement for the low molecular weight interstitial reference; it has a space distribution indistinguishable from that for [14C]sucrose. [14C]urea and 3H2O, which distribute similarly in red blood cells, have similar outflow dilution profiles. With corrections for minor deviations in recovery [a ratio of 0.936 +/- 0.024 (SD)] and transit time [a ratio of 0.962 +/- 0.008 (SD)], the cellular water space can be closely approximated from the [14C]-urea curve. 58Co-EDTA and [14C]urea are reasonable substitutes for [14C]sucrose and 3H2O, respectively, in multiple indicator dilution liver perfusion studies for investigating transfer and removal characteristics of tracer substrates.