Drug transport and metabolism of novel anticancer drugs

Many anticancer drugs need to be metabolized in order to exert their action, including the antitumor effect but unfortunately metabolism may also result in the formation of toxic metabolites. Metabolism may also change the physicochemical properties of a molecule so that it may or may not become a substrate for one of the efflux pumps, such as the ABC transporters, including P-glycoprotein, the multidrug resistance proteins and the breast cancer resistance protein (BCRP) [1]. This can lead to unwanted accumulation in normal tissues resulting in toxicity. These usually poor physico-chemical properties [2] also determine whether a compound will be a substrate for one of the many influx transporters, such as the organic cation transporters or the organic anion transporters. Although metabolism was recognized to be an important aspect in tumor development (e.g., according to the Warburg hypothesis) and drug metabolism, these properties tended to be neglected in drug development in the last decade of the twentieth and the first of twenty-first century. Early anticancer drug development focused on the increased need of tumor cells for DNA synthesis, leading to drugs that alter the synthesis of DNA and RNA precursors, such as the antimetabolites [3], or drug affecting the DNA structure, such as alkylating agents, anti-tubulins and platinum analogs. Both serendipity and rational drug design played major roles in drug development with nitrogen mustards and methotrexate, respectively, as classical examples [4]. However, for all these drugs, possibly by their nature, it was recognized that metabolism plays a major role in antitumor activity, resistance and toxicity. In the early stages of the development of protein kinase inhibitors, the focus was on the target and only protein kinase inhibitors were considered as targeted therapy or even molecular targeted therapy, neglecting that the classical antifolate methotrexate has only one target, dihydrofolate reductase [5], and that hormonal therapy was targeted against, for example, the estrogen receptor [6]. Moreover, one of the major molecules in the cell, DNA, is targeted by drugs like cisplatin and oxaliplatin [7], which can be considered as an early example of molecular targeted therapy. Neglecting the important role of metabolism in the pharmacology of any drugs was a major drawback in the early development of protein kinase inhibitors, resulting in poorly designed clinical trials and unexpected serious or even life-threatening toxicities. Moreover, most of the targeted therapies appeared to be multitargeted [8], and only recently it is being recognized that targeted therapy might be effective in several tumors because of its multitargeted nature [2]. Tumor cells are characterized by the presence of multiple altered signaling pathways, so that protein kinase inhibitors can lead to an un-intended paradoxical activation of other signaling pathways, either directly or via feedback loops [2]. This robustness can be considered a hallmark of a cancer cell. Therefore a multitargeted protein kinase inhibitor is more likely to be effective than a specific mono-targeted drug [8]. Only tumors that are dependent on one specific mutation or translocation (e.g., bcr-abl) are likely to be sensitive to a relatively specific protein kinase inhibitor, such as imatinib [9], whose efficacy is negatively influenced by its metabolism and by being a substrate for efflux transporters [10]. Crizotinib is targeted against ALK, but in addition shows favorable pharmacokinetics [11]. Another advantage can be achieved when the metabolite of a drug would inhibit another target,