Portal-systemic spill-over of bile acids: a study of mechanisms using ursodeoxycholic acid

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Abstract
Portal-systemic spill-over of unconjugated ursodeoxycholic acid (UDCA) was assessed in 10 healthy subjects, 6 patients with mild chronic liver disease and 8 patients with cirrhosis. Following oral administration of UDCA (1.5 mg/kg body wt), serum concentrations of unconjugated UDCA were measured during 2 h using a capillary GLC method. Peak time of UDCA varied for 15-30 min, but was not significantly different in the 3 groups studied. Peak concentration was increased up to 2-fold in patients with mild, and up to 3-fold in patients with cirrhotic liver disease. Since, in addition, plasma disappearance rate (k) was markedly impaired in cirrhotics (1.7 .+-. SD 0.5%/min, compared to 2.8 .+-. 0.6 in healthy controls), the calculated area under the curve (AUC) was on the average 5-fold that in conrols. In 2 healthy and 4 cirrhotic subjects, the data obtained after oral administration were compared with those after i.v. loading with the same UDCA dose. The k-values after the 2 routes of administration were practically identical. Calculated systemic availability was 50% in normals, 78-87% in cirrhotics, 90 and 136% in 2 patients with surgical portacaval shunt. The portal-systemic spill-over of UDCA in patients with liver disease is increased primarily due to portal-systemic shunting. Since in the normal liver hepatic extraction of conjugated, endogenous bile acids is > 80%, diminished 1st-pass elimination is expected to augment systemic concentrations even more, particularly when measured after a meal.