Parameters affecting the hepatobiliary clearance of Tc-99m N(2,6-dimethylphenyl carbamoylmethyl) iminodiacetic acid (Tc-HIDA) were evaluated in dogs. Competitive clearance studies, were performed with Tc-HIDA after infusion to plasma saturation levels of an anion, sodium sulfobromophthalein (BSP), and a cation, oxyphenonium. The results demonstrated that Tc-HIDA is transported through hepatocytes by a carrier-mediated organic-anion pathway. The data are consistent with an alteration of the elimination kinetics of Tc-HIDA induced by elevations in the serum bilirubin level, and it is predicted that serum bilirubin at some increased concentration will dominate the distribution and elimination kinetics of Tc-HIDA independently of hepatobiliary status. A quantitative description of liver function in terms of regional distribution and elimination rate constants will require either a pharmacokinetic model that expressly includes the effects of bilirubin, the development of new anionic hepatobiliary agents capable of displacing endogenous bilirubin from transport binding sites, or the development of new hepatobiliary agents that use a different clearance mechanism from that used by bilirubin.