Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski's Rule of Five

Many studies have shown that toxicities of anticancer drugs and their adverse effects are related to their chemical structure and high molecular weight that may result in a number of metabolites interacting with drug offtarget networks. These factors require further attention for advancing cancer treatment and decreasing toxicities caused by the molecular complexity of antineoplastic agents. Providing more target-selective and tolerable cancer therapy with fewer side effects would not only improve patients' compliance, but also would decrease cancer-remission rates. This review presents several antineoplastic agents and their metabolites with molecular weights greater than 500 g/mol, which reportedly cause more than fifteen types of adverse reactions during breast cancer therapy.