Sex difference in the hepatic uptake of sulphobromophthalein (BSP) was investigated in male and female rats in three different experimental models. In the intact animal the BSP plasma disappearance rate was significantly higher (P less than 0.01) in females than in males when 0.15 or 1.5 mumol/kg body wt. was injected. Comparable values were found at the highest BSP dose (15 mumol/kg body wt.) used. In the perfused liver, the first-pass hepatic extraction and the uptake velocity were significantly higher (P less than 0.001) in female rats at low BSP doses (0.3-750 mumol/g of liver) whereas identical values were found at higher concentrations. In hepatocytes isolated by collagenase perfusion, the BSP uptake occurs via two different uptake sites in both sexes. The Km of the high affinity sites was lower in females than in males (3.67 +/- 0.58 vs 7.24 +/- 0.68 mumol/l, P less than 0.001) whereas Vmax. showed comparable values (2.70 +/- 0.36 vs 2.47 +/- 0.45 nmol of BSP/mg of protein, NS). In contrast, no difference was found in the kinetic parameters of the low affinity sites (Km 50.6 +/- 31.1 vs 61.0 +/- 17.5 mumol/l; Vmax. 21.9 +/- 13.2 vs 25.0 +/- 3.6 nmol of BSP/mg of protein, mean +/- SD, NS, females and males respectively). Taken together these data show that low doses of BSP are taken up by the liver more efficiently in female than in male rats and are consistent with a sex-related difference in the affinity but not in the number of the BSP high affinity uptake sites.