Determination of Human Serum α1-Acid Glycoprotein and Albumin Binding of Various Marketed and Preclinical Kinase Inhibitors

Abstract

There are about 380 protein kinase inhibitors in drug development as of today and 15 drugs have been marketed already for the treatment of cancer. This time 139 validated kinase targets are in the focus of drug research of pharmaceutical companies and big efforts are made for the development of new, druglike kinase inhibitors. Plasma protein binding is an important factor of the ADME profiling of a drug compound. Human serum albumin (HSA) and alpha(1)-acid glycoprotein (AAG) are the most relevant drug carriers in blood plasma. Since previous literature data indicated that AAG is the principal plasma binding component of some kinase inhibitors the present work focuses on the comprehensive evaluation of AAG binding of a series of marketed and experimental kinase inhibitors by using circular dichroism (CD) spectroscopy approach. HSA binding was also evaluated by affinity chromatography. Protein binding interactions of twenty-six kinase inhibitors are characterized. The contribution of AAG and HSA binding data to the pharmacokinetic profiles of the investigated therapeutic agents is discussed. Structural, biological and drug binding properties of AAG as well as the applicability of the CD method in studying drug-protein binding interactions are also briefly reviewed.

Functional and Clinical Evidence of the Influence of Sorafenib Binding to Albumin on Sorafenib Disposition in Adult Cancer Patients

“…By using the induced circular dichroism (ICD) spectroscopy, Zsila et al previously reported AAG and albumin values of sorafenib Kd which are approximately 2-and 100-fold higher than ours, respectively (13). Differing experimental conditions may account for the large discrepancy in albumin values of sorafenib Kd between the two investigations.…”

“…In this context, characterizing the sorafenib binding to albumin is of critical pharmacological and clinical interest. Finally, Zsila et al recently showed that sorafenib also binds to α1-acid glycoprotein (AAG) (13), although this result is in disagreement with the data provided by the manufacturer of sorafenib (11). As serum AAG concentration can be increased by 1.6-3.0 fold in several neoplasia, AAG may potentially be a parameter influencing sorafenib CL.…”

In SilicoADME/Tox Predictions

“…The level of AAG is increased in neoplasms, while HSA is markedly depressed in progressive malignancies [187].…”

“…HSA binding has been intensively investigated [41,186,187]. HSA is a singlechain protein that contains several binding sites for drugs, including site I and site II (indole-benzodiazepine site) (Figures 2.16 and 2.17).…”

“…The majority are basic compounds such as beta-blockers, but neutral and acidic molecules such as steroid hormones or the anticoagulant coumarin molecules may also bind. Genetic variability of AAG adds even more variability to its ligand-binding properties [187]. Several studies were reported that attempt to predict HSA binding using known HSA binders and QSAR [189,190].…”