RT Journal Article
SR Electronic
T1 Mechanism of Chloroquine Transport in the Isolated Retina
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 99
OP 112
VO 13
IS 1
A1 DONALD J. BEDNARCZYK
A1 FEDOR MEDZIHRADSKY
YR 1977
UL http://molpharm.aspetjournals.org/content/13/1/99.abstract
AB The feasibility of using the isolated rat retina to study transport processes was ascertained. The incubated tissue was characterized by a constant extracellular space, high steady-state levels of energy reserves, and high ratio of cellular K+ to Na+. The mediated transport system for chloroquine was experimentally resolved from total drug uptake and was distinguished from the nonsaturable uptake component as well as from tissue binding. The saturable uptake process had an apparent Km and Vmax of 2.4 mM and 8 nmoles/mg, dry weight, per minute, and resulted in retinal accumulation of chloroquine relative to its concentration in the medium. The uptake was independent of monovalent cations and displayed a Q10 of 1.62. Metabolic inhibitors and ouabain strongly enhanced the rate of chloroquine uptake. Exposure of the retina to these substances abolished the characteristics of the saturable transport system and resulted in drug uptake by a markedly stimulated, nonmediated process, apparently because of increased permeability of the plasma membrane. The saturable uptake increased at high pH, the data indicating an uncharged form of the drug during transport. Both uptake and exodus of chloroquine displayed the phenomenon of countertransport. Cellular disruption altered the sensitivity of uptake to temperature and pH, and abolished drug accumulation as well as countertransport. Quinacrine, amphetamine, and cocaine, but not biogenic amines, competitively inhibited the uptake of chloroquine and transaccelerated its transport. The results provide evidence for the existence in the retina of a mediated transport system for drugs structurally related to basic amines.