Dysfunction in tyrosine kinase activity disrupts the nor-mal control of cellular phosphorylation signaling pathways,which plays a vital role in genesis and development of various tumors, and makes tyrosine kinases a class of targets of many anti-tumor drugs. Currently most approved tyrosine kinase inhibitors ( TKIs) are based on irreversible binding mechanisms, making them poorly selective, not potent or sustained enough regarding pharmacological effects and prone to triggering resistance. In the past decade, much progress has been made in the development of
a new class of TKIs which irreversibly inhibit their target proteins via the formation of covalent bonds, overcoming the drawbacks of irreversible TKIs. Several irreversible TKIs have entered markets or clinical research phases. This review is to summarize the structural, pharmacological and medicinal chemical properties of investigational and marketed irreversible TKIs as well as their re-cent developments.

Antibody-drug conjugate (ADC) is a new class of therapeutics composed of a monoclonal antibody and small cytotoxin moieties conjugated through a chemical linker. ADC molecules bind to the target antigens expressed on the tumor cell surfaces guided by the monoclonal antibody component. The binding ADC molecules can be internalized and subsequently the toxin moieties can be released within the tumor cells via chemical and/or enzymatic reactions to kill the target cells. The conjugation combines the merits of both components, i.e., the high target specificity of the monoclonal antibody and the highly potent cell killing activity of the cytotoxin moieties. However, such complexities make the pharmacokinetic and metabolic studies of ADCs highly challenging. The major challenges should include characterization of absorption, distribution, metabolism and excretion, investigation of underlying mechanisms, assessment of pharmacokinetic- pharmacodynamic relationship, and analytical method development of ADC drugs. This review will discuss common pharmacokinetic issues and considerations, as well as tools and strategies that can be utilized to characterize the pharmacokinetic and metabolic properties of ADCs.