Effect of protein binding on renal extraction of I-131-OIH and Tc-99m-labeled tubular agents

The clearance of Tc-99m-mercaptoacetyltriglycine (MAG3) is less than the cl earances of o-I-131-iodohippurate (OIH) and Tc-99m-labeled DD- and LL-ethyl enedicysteine (EC). This difference could be associated with the lower affi nity of MAG3 for the tubular transport receptor, but MAG3 is more highly pr otein bound than OIH and the EC isomers; protein binding could also be an i mportant factor governing tubular extraction. To separate the effects of pr otein binding from tubular receptor affinity, the extraction fractions (EFs ) of MAG3, OIH, and the DD, LL, and DL isomers of Tc-99m-EC were measured i n an isolated perfused rat kidney model using a protein-free perfusate and perfusates containing bovine serum albumin. Methods: The right kidney was r emoved from the rat and perfused with modified Krebs-Henseleit buffers cont aining 7.5 or 2.5 g/dL bovine serum albumin or a protein-free perfusate. OI H was coinjected into the renal artery with each of the Tc-99m-tracers. Pro tein binding was measured in each of the perfusates, and the venous outflow was collected to determine the EF. Results: The protein binding of MAG3 in the albumin perfusates ranged from 87% to 95%, significantly higher than t he 20%-34% range of protein binding observed with the three EC complexes (P < 0.05). In the 2.5 g/dL albumin perfusate, the EF of MAG3 was 44%, signif icantly less than the 57%-77% EF of the three EC complexes; in the 7.5 g/dL perfusate, the MAG3 EF fell to 18% versus 39%-45% for the EC complexes (P < 0.05). However, in the protein-free perfusate, the EF of MAG3 was 64%, eq ual to or higher than the 46%-62% EF of the three EC complexes. Conclusion: Protein binding modulates the tubular extraction of renal tracers. Protein binding and receptor affinity must be considered in the design of future r enal radiopharmaceuticals as well as radiopharmaceuticals targeting other r eceptors.