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Rapid CommunicationShort Communication

The Nonspecific Binding of Tyrosine Kinase Inhibitors to Human Liver Microsomes

Kushari Burns, Pramod C. Nair, Andrew Rowland, Peter I. Mackenzie, Kathleen M. Knights and John O. Miners
Drug Metabolism and Disposition December 2015, 43 (12) 1934-1937; DOI: https://doi.org/10.1124/dmd.115.065292
Kushari Burns
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
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Pramod C. Nair
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
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Andrew Rowland
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
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Peter I. Mackenzie
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
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Kathleen M. Knights
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
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John O. Miners
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
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Abstract

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.

Footnotes

    • Received May 4, 2015.
    • Accepted October 5, 2015.
  • This study was supported by a project grant [1044063] from the National Health and Medical Research Council of Australia.

  • dx.doi.org/10.1124/dmd.115.065292.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (12)
Drug Metabolism and Disposition
Vol. 43, Issue 12
1 Dec 2015
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Rapid CommunicationShort Communication

The Nonspecific Binding of Tyrosine Kinase Inhibitors to HLM

Kushari Burns, Pramod C. Nair, Andrew Rowland, Peter I. Mackenzie, Kathleen M. Knights and John O. Miners
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1934-1937; DOI: https://doi.org/10.1124/dmd.115.065292

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Rapid CommunicationShort Communication

The Nonspecific Binding of Tyrosine Kinase Inhibitors to HLM

Kushari Burns, Pramod C. Nair, Andrew Rowland, Peter I. Mackenzie, Kathleen M. Knights and John O. Miners
Drug Metabolism and Disposition December 1, 2015, 43 (12) 1934-1937; DOI: https://doi.org/10.1124/dmd.115.065292
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