1. The two well-known methods of estimating rates of irreversible disposal (R) of blood-borne substrates in vivo by isotope experiments involve estimating the specific radioactivity (S) of the substrate in blood either after single intravenous injection of labelled substrate or during its infusion at a constant rate. The value of R is calculated from the S–time curve, usually by assuming: (i) a metabolic steady state with respect to substrate, (ii) the passage of all substrate through the blood, and (iii) the absence of certain types of recycling via blood. 2. In a theoretical investigation we show how experiments can be performed and R calculated from analyses of blood when one or more of the above assumptions is unjustified, by using glucose, ketone bodies, plasma free fatty acids and proteins as examples. In general the methods require single injection procedures, with estimation of the total quantity of label in the substrate in blood and the substrate concentration instead of only S. Such values give estimates of R with standard errors even when only one blood specimen is taken from each of a group of animals, as is convenient when working with small animals or substrates in low concentration, and when the animals are in a non-steady state in which constant infusion procedures are invalid. 3. Similar methods give the fraction of label injected as one compound which passes through another (the isotopic yield). 4. The methods are not always applicable, and cannot be applied to plasma proteins in some pathological conditions. A questionnaire for assessing their applicability is given.

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