Cellular Distribution of Drugs
We have established cell models for predicting mechanisms of drug transport and metabolism. These models include stably transfected cell lines that overexpress efflux or uptake transporters, such as MDCK-Pgp and HEK293-OATPs. We routinely isolate fresh human hepatocytes, which can be used for combined transport and metabolism studies. Hepatocytes can be used in simple suspensions, as well as in complex 3D models such as sandwich-cultured human hepatocytes (SCHH) or spheroid configurations.
Intracellular Bioavailability
New analyses developed in our laboratory enable the determination of intracellular bioavailability (Fic). Fic is the result of the net effect of all cellular drug disposition processes and represents the concentration of unbound drug available inside the cell compared to the concentration outside the cell. This method allows for accurate prediction of drug access to intracellular targets in a wide variety of cell types, without prior knowledge of the involved drug distribution pathways. It is applicable for high-throughput determinations and utilizes membrane dialysis and sensitive analysis with ultra-performance liquid chromatography and mass spectrometry.
The liver is a crucial organ for removing xenobiotics, such as drugs, from the bloodstream. Transport and metabolic functions are primarily carried out by hepatocytes, the parenchymal cells of the liver, which make up about 80% of the liver volume. Non-parenchymal cell types (NPCs) include endothelial cells in the liver sinusoid, liver macrophages known as Kupffer cells, and specialized pericytes called hepatic stellate cells. NPCs help regulate hepatocyte function and are involved in many liver diseases. In our lab, we use human liver cells in various in vitro systems to study drug disposition in the liver. Proteomic analysis is an important aspect of this work, which we use to better understand how hepatocytes uptake and metabolize drugs, and to clarify the roles played by other cell types in these vital processes.
Contact
- Visiting Address: BMC, Husargatan 3, A1:2, A2:2, A3:3, B3:3, B3:4, C2:2
- Letter and Postal Address: Box 580, SE-751 23 Uppsala