The potential of erythrocytes (RBC) to serve as "barriers" of hepatic elimination of propranolol, a drug with rapid equilibration in blood, was studied in rats under two conditions: (I) the drug was preequilibrated in blood before infusion into the liver, and (II) the drug was directly infused into the liver. The mean fractions of dose escaping elimination during each pass under conditions I and II were 0.0561 +/- 0.040 and 0.0290 +/- 0.024, respectively (P less than 0.02). Contrary to the early study on doxorubicin, most drug molecules in RBC were found to be available for elimination. Implications of the present findings in the prediction of hepatic first-pass effect after oral administration, on the basis of intravenous data, are discussed. Marked underestimation of oral bioavailability of propranolol in humans is consistent with the RBC "barrier" effect hypothesis.