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Effect of cholestasis on hepatic transport of 99mtechnetium p-isopropyl-iminodiacetic acid.

Hepatobiliary imaging with 99mTc-p-isopropyl-iminodiacetic acid (PIPIDA) and other acetanilidoiminodiacetic acid derivatives is a frequently used clinical tool in evaluating patients with jaundice. However, there has been little objective assessment of the effects of cholestasis on hepatic transport of acetanilioiminodiacetic acid derivatives. In our studies, transport of 99mTc-PIPIDA by isolated rat hepatocytes obtained from animals with extrahepatic obstruction secondary to bile duct ligation or intrahepatic cholestasis induced by ethinyl estradiol therapy was determined. Uptake constants for 99mTc-PIPIDA by hepatocytes isolated from livers of animals with ligated bile ducts were significantly decreased compared with uptake by liver cells from sham-operated controls (0.0030 +/- 0.0003 vs. 0.0089 +/- 0.0010 femtomole X 10(6) cells-1 X min-1 X pmol/L-1; p less than 0.001). Hepatocytes isolated from livers of animals given ethinyl estradiol also demonstrated significantly reduced 99mTc-PIPIDA uptake compared with controls given propylene glycol (0.0034 +/- 0.0002 vs. 0.0060 +/- 0.0004 fmol X 10(6) cells-1 X min-1 X pmol/L-1; p less than 0.001). Fractional rates of efflux of the study compound from hepatocytes preincubated with 99mTc-PIPIDA were significantly decreased in experiments using ethinyl estradiol (p less than 0.005) but did not differ significantly from controls in studies of bile duct ligation. 99mTc-PIPIDA uptake was significantly decreased in the presence of high bile salt concentrations (100 to 200 mumol/L), but unconjugated bilirubin concentrations as high as 200 mumol/L (approximately 12 mg/dl) had no effect on hepatocyte uptake of the ligand. The finding that cholestasis significantly impairs hepatocyte uptake of 99mTc-PIPIDA provides a possible explanation for the clinical observation that a patent biliary tree and normal serum bilirubin level are not always sufficient to ensure normal hepatobiliary imaging. These data also suggest that elevation of bile acid levels during cholestasis may either contribute to impaired uptake of hepatobiliary imaging agents or serve as a marker of cholestasis-induced abnormalities in the liver functions responsible for hepatic transport of these compounds.