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The effect of high-protein meal on the hepatic clearance (ClH) of intravenous lidocaine, because of its conceptual importance in understanding first-pass metabolic phenomena, was evaluated in nine healthy males. Our randomized crossover study demonstrated that mean ClH rose from 1245 to 1477 ml/min (P less than 0.03) as a result of the meal (i.e., mean area under the blood concentration-time curve decreased 20%). The magnitude of the change in clearance correlated weakly with fasting ClH (r = 0.54; slope = -0.037% per ml/min; intercept = 67.2%; P less than 0.15). In a separate study, it was observed that the meal did not influence lidocaine serum protein binding; the free fraction of lidocaine in samples drawn from the subjects in the fasting state averaged 0.305 +/- 0.027 while that from subjects who had eaten was 0.321 +/- 0.042. These data suggest that the mean clearance of lidocaine is increased by stimulation of hepatic blood flow rate. Furthermore, the magnitude of this increase is consistent with expectations based on a simple physiologic model. Thus, these data provide experimental support for the hypothesis that transient increases in splanchnic blood flow rate observed after a high-protein meal may explain apparent improvement of the oral bioavailability of model high intrinsic clearance drugs.