Plasma clearance and organ distribution of intravenously injected human recombinant [125I]interleukin (IL)-6 and [125I]tumor necrosis factor (TNF)-alpha were studied in male rats, 2 hr after intravenous alcohol (ethanol) administration (single dose, 2.2 g.kg-1 body weight). Also, the rate of uptake and degradation of the two cytokines by the isolated, perfused rat liver was studied in the absence or in the presence of ethanol (35 mM) in the perfusate. Acute ethanol administration significantly increased plasma clearance rate for both cytokines (36% and 72%, for IL-6 and TNF-alpha, respectively), decreased the t1/2 alpha (30% and 11%, for IL-6 and TNF-alpha, respectively), abolished the slow (beta)-phase component for TNF-alpha, and increased t1/2 beta for IL-6 (31%). Although alcohol did not affect organ distribution of TNF-alpha, it increased the IL-6 content in the liver, kidney, and blood. IL-6 uptake rate by the isolated, perfused rat liver was 2-fold higher than TNF-alpha uptake, whereas the rate of degradation was larger for TNF-alpha than for IL-6, despite the fact that both cytokines were presented to the liver at the same concentration (6 nM). Ethanol addition to the perfusate (35 mM, final concentration) significantly increased TNF-alpha uptake (24%), without affecting IL-6 uptake or the degradation rate of either cytokine. Also, the kinetics of degradation by the isolated, perfused rat liver was linear for TNF-alpha, but exponential for IL-6. Data presented in this study demonstrate that: (1) acute alcohol consumption can alter the kinetic behavior of IL-6 and TNF-alpha in the bloodstream, mainly by accelerating their clearance which, in turn, may counteract the outcome of cytokine secretion and delivery to the blood; and (2) short exposure of liver to ethanol levels commonly seen in humans after binge drinking may alter its capacity to take up cytokines.