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Hepatocellular uptake of cyclosporin A by simple diffusion
K Ziegler1, G Polzin, M Frimmer
1Institut für Pharmakologie und Toxikologie, Justus Liebig Universität Giessen, F.R.G.
Biochimica Et Biophysica Acta
|February 8, 1988
Summary
Cyclosporin A uptake by liver cells is not carrier-mediated. However, this immunosuppressant drug non-competitively inhibits bile salt transport, impacting bile acid uptake.
Area of Science:
- Hepatology
- Pharmacology
- Biochemistry
Background:
- Cyclosporin A is primarily eliminated through the bile after liver biotransformation.
- The mechanism of liver cell uptake for Cyclosporin A, whether passive diffusion or active transport, remained unclear.
Purpose of the Study:
- To investigate the mechanism of Cyclosporin A uptake by liver cells.
- To determine if Cyclosporin A competes with other transport systems, potentially explaining drug-induced cholestasis.
Main Methods:
- Experiments utilizing [3H]Cyclosporin A were conducted on isolated rat hepatocytes.
- Uptake kinetics were analyzed to assess saturation and energy dependence.
Main Results:
- Cyclosporin A uptake by hepatocytes was found to be neither saturable nor dependent on metabolic energy.
- Cholestasis induced by Cyclosporin A is not due to competition for a carrier protein.
- Cyclosporin A demonstrated non-competitive inhibition of bile salt uptake, indicating interaction with the bile acid transport system.
Conclusions:
- Cyclosporin A uptake into liver cells occurs via passive diffusion, not carrier-mediated transport.
- The drug-induced cholestasis is not a result of carrier competition.
- Cyclosporin A interferes with the bile acid transport system through non-competitive inhibition of bile salt uptake.