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ABC Transporters in Multi-Drug Resistance and ADME-Tox of Small Molecule Tyrosine Kinase Inhibitors

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Abstract

The past decade has seen tremendous efforts in the research and development of new chemotherapeutic drugs using target-based approaches. These efforts have led to the discovery of small molecule tyrosine kinase inhibitors (TKIs). Following the initial approval of imatinib by the US FDA in 2001, more than 15 TKIs targeting different tyrosine kinases have been approved, and numerous others are in various phases of clinical evaluation. Unlike conventional chemotherapy that can cause non-discriminating damage to both normal and cancerous cells, TKIs attack cancer-specific targets and therefore have a more favorable safety profile. However, although TKIs have had outstanding success in cancer therapy, there has been increasing evidence of resistance to TKIs. The enhanced efflux of TKIs by ATP-binding cassette (ABC) transporters over-expressed in cancer cells has been found to be one such important resistance mechanism. Another major drawback of TKI therapies that has been increasingly recognized is the extensive inter-individual pharmacokinetic variability, in which ABC transporters seem to play a major role as well. This review covers recent findings on the interactions of small molecule TKIs with ABC transporters. The effects of ABC transporters on anticancer efficacy and the absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of the small molecule TKIs are summarized in detail. Since TKIs have been found to not only serve as substrates of ABC transporters, but also as modulators of these proteins via inhibition or induction, their influence upon ABC transporters and potential role on TKI-drug interactions are discussed as well.

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Abbreviations

ABC:

ATP-binding cassette

ADME-Tox:

Absorption, distribution, metabolism, excretion, and toxicity

ALL:

Acute lymphoblastic leukemia

BCRP:

Breast cancer resistance protein

CML:

Chronic myelogeous leukemia

EGFR:

Epidermal growth factor receptor

MDR:

Multi-drug resistance

MRP1:

Multi-drug resistance protein 1

PDGFR:

Platelet-derived growth factor receptor

P-gp:

P-glycoprotein

SAR:

Structure activity relationship

TKIs:

Tyrosine kinase inhibitors

VEGFR:

Vascular endothelial growth factor receptor

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  1. Department of Pharmaceutics, College of Pharmacy, University of Florida, 6550 Sanger Road, Orlando, Florida, 32827, USA

    Jiexin Deng, Jie Shao & Guohua An

  2. Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, USA

    John S. Markowitz

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Deng, J., Shao, J., Markowitz, J.S. et al. ABC Transporters in Multi-Drug Resistance and ADME-Tox of Small Molecule Tyrosine Kinase Inhibitors. Pharm Res 31, 2237–2255 (2014). https://doi.org/10.1007/s11095-014-1389-0

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