The role of deuteration in enhancing anticancer therapy: Mechanisms, pharmacokinetics, and clinical updates.

Cancer is still a leading cause of mortality worldwide and thus more effective and less toxic therapeutic regimens are constantly required. Modern chemotherapeutic agents commonly suffer from a narrow therapeutic window, the potential for severe adverse drug reactions, and lack of metabolic stability which can lead to either decreased exposure at the target site or selective exposure to toxic metabolites. Deuteration is the process of replacing hydrogen (1H or H) with deuterium (D), a heavy and stable isotope of hydrogen, which creates a unique chemical avenue to enhance the bioavailability, pharmacokinetics (PK) and safety profile of both new and existing anticancer agents. This improvement is mainly due to the kinetic isotope effect (KIE), which significantly augments C - D bonds in comparison with C - H bonds, and hence retards enzymatically catalyzed oxidative metabolism by CYP enzymes. This review summarizes the key principles of deuteration, discusses its use in increasing the potency and decreasing toxicity of drugs (including a flavonoid apigenin, as well as several clinical candidates), and describes recently emerging applications of Deuterium Magnetic Resonance Imaging (dMRI) for non-invasive assessment of early tumor response to therapy. We finish with the advanced state of some deuterated anticancer drugs in preclinical and clinical development supporting that pharmacologic deuteration is a potent approach to exploiting certain drug metabolism pathways for improving oncology therapy.