The serum bile acid disappearance of tracer doses of [24-14C]cholic acid and [1-14C]glycocholic acid were studied in eight normal subjects and 11 patients with chronic liver disease (with or without cholestasis) in order to determine the effect of liver disease on hepatic clearances, reflux of conjugated cholic acid and initial distribution volume of each tracer. Total cholic acid clearance was significantly reduced from normal (7.2 ± 0.7 ml min-1 kg-1, mean ± SE) in patients with liver disease 69-88% group means) as were unconjugated cholic acid (51-68%) and glycocholic acid (66-83%) clearance. Extensive regurgitation of labeled conjugated cholic acid (after unconjugated cholic acid tracer injection) among cholestatic patients accounted for 69 ± 5% of total 14C remaining in serum at 70 min, thus masking a less-impaired uptake process. The hepatic extraction efficiency for conjugated cholic acid among controls (86 ± 8%) was greater than that for unconjugated cholic acid (60 ± 4%), and was greatly reduced among patients (7-27%, group means). Normal subjects and patients with cirrhosis without cholestasis did not distribute the isotope to extravascular, extrahepatic spaces, in contrast to cholestatic patients with serum bile acid concentration > 149 μmol/l. Careful evaluation of serum disappearance of bile acids as well as chromatographic separation of regurgitated metabolites, could provide investigators with indirect evidence of defects in the rate-limiting steps (uptake, conjugation or excretion) of hepatic bile acid transport.