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Biopharmaceutical study of the hepato-biliary transport of drugs. I. Hepato-biliary transport of non-metabolizing organic anionic compounds in rat.

Bromphenol blue (BPB) and p-acetylaminohippuric acid (PAAH) were studied with rats to understand the basic principles of hepato-biliary transport process. At higher doses of BPB, the hepato-biliary transport capacity appeared to be saturated. At 30 min after the intravenous administration of BPB (5 μmole/300 g body weight), bile/plasma concentration ratio (B/P ratio) was 894±99, liver/plasma concentration ratio (L/P ratio) was 22±5 and bile/liver concentration ratio (B/L ratio) was 42±8. In the case of PAAH (6 μmole/300 g), B/P ratio was 43±15, L/P ratio was 0.47±0.27 and B/L ratio was 12±30. Sulfobromophthalein (BSP) inhibited the L/P and B/L ratios of BPB and BPB inhibited the L/P and B/L ratios of PAAH. With rat liver cell suspensions, BPB was entrapped very rapidly and its cell/medium concentration ratio was about 21 at 30 μg/ml, which was depressed by BSP. With equilibrium dialysis, 95.6±1.5% of BPB and 11.3±3.4% of PAAH were bound to the liver homogenate. These results suggest that these organic anions are transported from blood into bile at least two processes, namely hepatic uptake and biliary excretion, and that the hepatic uptake of these compounds is mainly due to the binding to the substances which exist in the liver cells.