The Nonspecific Binding of Tyrosine Kinase Inhibitors to Human Liver Microsomes
| Autor: | Kathleen M. Knights, Peter I. Mackenzie, John O. Miners, Andrew Rowland, Pramod C. Nair, Kushari Burns |
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| Rok vydání: | 2015 |
| Předmět: |
Niacinamide
Indazoles Pyridines Pharmaceutical Science Pharmacology Lapatinib chemistry.chemical_compound Regorafenib medicine Humans Equilibrium dialysis Protein Kinase Inhibitors Sulfonamides Phenylurea Compounds Dabrafenib Protein-Tyrosine Kinases Sorafenib respiratory tract diseases Axitinib Pyrimidines Biochemistry chemistry Nilotinib Microsomes Liver Erlotinib human activities Tyrosine kinase medicine.drug Protein Binding |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 43(12) |
| ISSN: | 1521-009X |
| Popis: | Drugs and other chemicals frequently bind nonspecifically to the constituents of an in vitro incubation mixture, particularly the enzyme source [e.g., human liver microsomes (HLM)]. Correction for nonspecific binding (NSB) is essential for the accurate calculation of the kinetic parameters Km, Clint, and Ki. Many tyrosine kinase inhibitors (TKIs) are lipophilic organic bases that are nonionized at physiologic pH. Attempts to measure the NSB of several TKIs to HLM by equilibrium dialysis proved unsuccessful, presumably due to the limited aqueous solubility of these compounds. Thus, the addition of detergents to equilibrium dialysis samples was investigated as an approach to measure the NSB of TKIs. The binding of six validation set nonionized lipophilic bases (felodipine, isradipine, loratidine, midazolam, nifedipine, and pazopanib) to HLM (0.25 mg/ml) was shown to be unaffected by the addition of CHAPS (6 mM) to the dialysis medium. This approach was subsequently applied to measurement of the binding of axitinib, dabrafenib, erlotinib, gefitinib, ibrutinib, lapatinib, nilotinib, nintedanib, regorafenib, sorafenib, and trametinib to HLM (0.25 mg/ml). As with the validation set drugs, attainment of equilibrium was demonstrated in HLM-HLM and buffer-buffer control dialysis experiments. Values of the fraction unbound to HLM ranged from 0.14 (regorafenib and sorafenib) to 0.93 (nintedanib), and were generally consistent with the known physicochemical determinants of drug NSB. The extensive NSB of many TKIs to HLM underscores the importance of correction for TKI binding to HLM and, presumably, other enzyme sources present in in vitro incubation mixtures. |
| Databáze: | OpenAIRE |
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