Albumins with new functions and clinical applications.

The focus of DMPK Theme Issues is state of the art and recent developments in research areas that have significant relevance for the academic world as well as for the pharmaceutical industry. The three issues that have appeared to date deal with drug-metabolizing enzymes, membrane transporters and pharmacokinetics and phar-macodynamics. This issue is dedicated to a water-soluble protein transporter, namely human serum albumin (HSA), and presents strategies for utilizing its unique ligand binding capability, and the latest news concerning its metabolism. This information can be useful in terms of the development of new compounds – drugs, albumins or albumin-ligand complexes – that can be used diagnostically or therapeutically. A considerable proportion of compounds with other biological activity fails to progress to later stages of drug development due to problems associated with absorption , distribution, metabolism and elimination (ADME). Because ADME is a complex issue, the cost of development of new drugs is increased considerable. This factor constitutes one of the main driving forces in the search for techniques to improve ADME characteristics in the early stages of drug development. The ligand binding properties of HSA and its abundance in the body couples the protein closely to the ADME problem. Therefore, detailed information regarding binding sites and ligand-induced conformational changes of HSA are critical to solving this problem. Recent X-ray crystallography and site-directed mutagenesis studies have contributed significant , new information in this area. Such information can be used to determine whether a new drug in spe should be constructed in such a way that it makes use of, or avoids, albumin transport and depot function. Molecular information is also very useful in related contexts, because it provids basic information on how to modify a protein or ligand for producing complexes with new properties. For example, modified albumin-heme complexes have the ability to reversibly bind to molecular oxygen; the aim of this research has been to construct an artificial hemoprotein. Furthermore, a complex of HSA and carboxy-C60-fullerene may become a useful pho-tosensitizer for photodynamic therapy of cancer. In addition to the reversible binding of ligands, HSA binds to xenobiotics and endogenous compounds in a covalent manner and thereby effects the metabolic fate and clearance of certain drugs. However, complex formation may produce a protein with new functions and possible clinical applications. Thus, HSA can be S-nitrosylated by nitric oxide, and the resulting compound may have antibacterial and cytoprotective properties. The production …