UCSF

It is important to accurately model drug disposition in the preclinical setting before novel drug compounds are introduced into humans. However, it is evident from current statistics on the drug development process that there is much room for improvement in the preclinical assessment of drug candidates in order to avoid clearance or toxicity issues when the drug is used in the clinic. One organ that plays a significant role in drug disposition and is therefore important to model is the kidney, which filters blood and is responsible for elimination of over one third of all drugs. The focus of this dissertation was to improve in vitro modeling of the kidney. First, multiple proximal tubule cell lines were systematically compared in order to identify the most physiologically relevant line. It was found that while the human cell lines hold some promise, non-human transfected cell lines remain more robust models of proximal tubule drug transport. Compared to the human cell lines, non-human transfected cell lines have superior monolayer formation, higher levels of transporter expression and function and are easier to grow in culture. Second, the role of one particular aspect of the in vivo environment, shear stress, was studied to better understand the effect on drug transporters and the possible biological pathways involved. Results indicated that shear stress affects active transport of organic cations and expression of relevant transporters in renal cells in a cilia dependent manner. Lastly, the design of a 1:1000 scaled model of the kidney that can be incorporated into a 1:1000 scaled human-on-a-chip system is presented along with the results of initial prototyping and future directions. In summary, the studies in this dissertation provide insight into the limitations of existing renal cell models, expand our current knowledge of the interaction between the cellular environment and drug transport functionality and provide a foundation for the future development of a scaled kidney on a chip module.