Fluid phase markers like erythritol and mannitol have been used to study canalicular bile secretion in the liver. It has recently been suggested that these molecules cross the ductular epithelium and thereby their biliary clearance may underestimate the canalicular bile flow. In the present study, the hepatic clearance of polyethylene glycol 900 (PEG 900), a fluid phase marker that has been used in studies of the kidney, was compared to the clearance of mannitol in the pig. We found that the hepatic clearance of PEG 900 exceeded that of mannitol by a factor of 55. After intravenous bolus injections, both mannitol and PEG 900 appeared within 1 min in bile while significant proportions of inulin were seen only after 7 min. The hepatic clearances of both mannitol and PEG 900 positively correlated to the bile acid secretion rate and were not affected by secretin infusion. The high hepatic clearance of PEG 900 compared to mannitol may be explained by a higher fluid flux into the canaliculi than previously estimated and a continuous ductular reabsorption of fluid and mannitol. Another possibility is an active transcellular vesicular transport of this molecule--an explanation that is not supported by the immediate appearance of PEG 900 in bile following an intravenous bolus injection nor by the finding that hepatic clearance of labeled PEG was not affected by a load of unlabeled marker.