Changes of net charge and α-helical content affect the pharmacokinetic properties of human serum albumin

The pharmacokinetics of 17 genetic variants of human serum albumin with single-residue mutations and their corresponding normal albumin were studied in mice. In all cases, the plasma half-life was affected, but only variants with + 2 changes in charge prolonged it, whereas changes in hydrophobicity decreased it. Good positive and negative correlations were found between changes in α-helical content taking place in domains I + III and domain II, respectively, and changes in half-lives. No correlation was found to type of mutation or to changes in heat stability as represented by ΔHv. Liver and kidney uptake clearances were also modified: α-helical changes of domains I + III showed good negative correlations to both types of clearances, whereas changes in domain II only had a good positive correlation to kidney uptake clearance. No correlation between the other molecular changes and organ uptakes was observed. The relatively few correlations between changes in molecular characteristics and the organ uptakes of the variants are most probably due to different handling by plasma enzyme(s) and the various types of cell endocytosis. Of the latter, most lead to destruction of albumin, but at least one results in recycling of the protein. The present information should be useful when designing recombinant, therapeutical albumins or albumin products with a modified plasma half-life.