Biomaterial Database

Kinetics of chloroquine uptake into isolated rat hepatocytes. 1993

A C MacIntyre, and D J Cutler

Department of Pharmacy, University of Sydney, Australia.

The kinetics of uptake of chloroquine into isolated rat hepatocytes were studied to further investigate whether they are consistent with accumulation of chloroquine at therapeutic concentrations that is predominantly due to lysosomal trapping. A mathematical model describing the disposition of weak bases in isolated hepatocytes was developed and fitted to the chloroquine uptake data, allowing estimation of permeability coefficients for un-ionized chloroquine transport across rate-limiting membranes (p0 = 5.9 +/- 0.5 cm. s-1). The results of these studies suggest that the lysosomal membrane is the rate-limiting membrane in uptake of chloroquine in isolated hepatocytes. The rate and extent of accumulation of chloroquine in isolated hepatocytes in the presence of 10 mM NH4Cl were decreased. These results are consistent with a reduction in lysosomal pH caused by NH4Cl. The kinetics of uptake of hydroxychloroquine, which is structurally similar to chloroquine, were also investigated. The results of these studies were also consistent with lysosomal trapping, although the p0 value for un-ionized hydroxychloroquine (p0 = 0.28 +/- 0.02 cm.s-1) was much lower than that for un-ionized chloroquine. The estimated p0 value for un-ionized chloroquine and hydroxychloroquine transport across the lysosomal membrane are of a similar magnitude to those reported for transport of these compounds across human erythrocyte membranes, suggesting a similar transport mechanism.

UI	MeSH Term	Description	Entries
D007700	Kinetics	The rate dynamics in chemical or physical systems.
D008099	Liver	A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.	Livers
D008247	Lysosomes	A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes MEMBRANE FUSION. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed).	Autolysosome,Autolysosomes,Lysosome
D008297	Male		Males
D008433	Mathematics	The deductive study of shape, quantity, and dependence. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)	Mathematic
D008954	Models, Biological	Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.	Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D002463	Cell Membrane Permeability	A quality of cell membranes which permits the passage of solvents and solutes into and out of cells.	Permeability, Cell Membrane
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D002738	Chloroquine	The prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses.	Aralen,Arechine,Arequin,Chingamin,Chlorochin,Chloroquine Sulfate,Chloroquine Sulphate,Khingamin,Nivaquine,Sulfate, Chloroquine,Sulphate, Chloroquine
D003593	Cytoplasm	The part of a cell that contains the CYTOSOL and small structures excluding the CELL NUCLEUS; MITOCHONDRIA; and large VACUOLES. (Glick, Glossary of Biochemistry and Molecular Biology, 1990)	Protoplasm,Cytoplasms,Protoplasms