In vivo estimates of nonoxidative leucine disappearance have frequently been used as estimates of leucine incorporation into protein. To attempt to assess this extrapolation to protein synthesis, seven overnight fasted dogs received primed 4-h infusions of emetine (3 mg/kg, 1 mg X kg-1 X h-1), an alkaloid known to inhibit protein synthesis at the translational level. Protein metabolism was studied using infusions of [1-14C]leucine and alpha-[4,5-3H]ketoisocaproate (KIC) and the steady-state specific activities of the leucine moiety (e.g., [14C]KIC and [3H]leucine) reciprocal to the infused isotopes as estimates of intracellular leucine specific activities. Plasma leucine (157 +/- 13 to 217 +/- 13 microM) and KIC (24 +/- 1 to 41 +/- 4 microM) concentrations increased (P less than 0.001), as did leucine oxidation (0.60 +/- 0.07 to 1.67 +/- 0.15 mumol X kg-1 X min-1, P less than 0.001). Estimates of nonoxidative leucine disappearance decreased (P less than 0.001) by approximately 70%, and estimates of the endogenous leucine rate of appearance decreased (P less than 0.001) by approximately 40% using either the 14C or 3H data. We conclude that, although in vivo estimates of leucine metabolism are not quantitative, rapid changes in whole-body estimates of protein synthesis can be predicted during infusion of labeled leucine.