ANALYSIS OF TIME COURSES OF METABOLIC PRECURSORS AND PRODUCTS IN HETEROGENEOUS RAT-BRAIN TISSUE - LIMITATIONS OF KINETIC MODELING FOR PREDICTIONS OF INTRACOMPARTMENTAL CONCENTRATIONS FROM TOTAL TISSUE ACTIVITY

The efficacy of various kinetic models to predict time courses of tota l radioactivity and levels of precursor and metabolic products was eva luated in heterogeneous samples of freeze-blown brain of rats administ ered [C-14]deoxyglucose ([C-14]DG). Two kinetic models designed for ho mogeneous tissues, i.e., a no-product-loss, three-rate-constant (3K) m odel and a first-order-product-loss, four-rate-constant (4K) model, an d a third kinetic model designed for heterogeneous tissues without pro duct loss [Tissue Heterogeneity (TH) Model] were examined. In the 45-m in interval following a pulse of [C-14]DG, the fit of the TH Model to total tissue radioactivity was not statistically significantly better than that of the 3K Model, yet the TH Model described the time courses of [C-14]DG and its metabolites more accurately. The TH- and 4K-Model -predicted time courses of [C-14]DG and its metabolites were similar. Whole-brain glucose utilization (CMR(glc)) calculated with the TH or 3 K Model, similar to 75 mu mol 100 g(-1) min(-1), was similar to values previously determined by model-independent techniques, whereas CMR(gl c) calculated with the 4K Model was 44% higher. In a separate group of rats administered a programmed infusion to attain a constant arterial concentration of [C-14]DG that minimizes effects of tissue heterogene ity as well as any product loss, CMR(glc) calculated with all three mo dels was 79 mu mol 100 g min(-1) at 45 min after initiation of the inf usion. Statistical comparisons of goodness of fit of total tissue radi oactivity were, therefore, not indicative of which models best describ e the tissue precursor and product pools or which models provide the m ost accurate rates of glucose utilization.