Contributions of Plasma Protein Binding and Membrane Transporters to Drug-Induced Mitochondrial Toxicity

Small molecules are optimally lipophilic in nature, which allows for transit through the circulation by binding to plasma proteins and passage through cellular membranes to gain access to intracellular targets. The molecular composition and architecture of mitochondria is also responsible for attracting certain small molecules that results in accumulation and impact on mitochondrial function. Binding to plasma protein provides a reservoir of the drug capable of providing a longer‐lasting reservoir of the drug compared with those more freely soluble in the bloodstream and may eventually accumulate in target tissues to a greater extent than the latter more hydrophilic drugs. Molecules transported by albumin are released in regions of low drug concentration. This mechanism enables drugs to be delivered to target tissues and enter into cells either by transport through specific plasma membrane transporters or via diffusion through the plasma membrane.