Although there are any number of specific examples, the first task is to establish general methods for determining which of the known carriers are most responsible for the cellular uptake of particular drugs, as a prelude to establishing the tissue distributions of the relevant carriers. The missing information required to understand the tissue distributions of drugs is thus represented by the specificities and location of uptake carriers. It is now increasingly recognized that drug uptake is predominantly carrier-mediated. While the role of carriers as mediators of drug efflux is well appreciated, uptake was, until recently, considered to be almost entirely a process of passive diffusion through the lipid part of the membrane and therefore largely determined by drug lipophilicity, with carrier uptake considered exceptional. The steady-state tissue distributions of drugs are determined by the rates of their uptake and efflux. Excessive concentration in particular tissues can be the cause of the former, while failure to reach targets can contribute to the latter. Of the many reasons for the attrition of candidate drugs during the development process, toxicity or lack of efficacy in vivo are among the most frequent. ConclusionsĪs well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells. To answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers. The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane.
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