The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia

The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial 99mTc-BROMIDA. Log P of 99mTc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to 99mTc-BROMIDA, 99mTc-DIETHYLIODIDA has: (a) better biliary excretion (2.76±0.15%ID/g versus 1.83±0.10%ID/g); (b) faster hepatic clearance (2.90±0.21%ID/g versus 7.47±0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15 min. It is proved that 99mTc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion.

► In this study we investigated the effect of lipophilicity on the hepatobiliary properties of IDA derivatives.
► Log P of alkyliodinated IDA derivatives and commercial IDA derivatives were calculated.
► Newly synthesized ligands with the highest calculated log P were labeled with 99mTc.
► Log P of those complexes were determined experimentally.
► The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats.