Renal secretion of organic cations: A multistep process

A wide variety of positively charged drugs and drug metabolites are very effectively excreted from the body via the renal organic cation transport system. Organic cation transport is a multistep process taking place in the proximal tubule, particularly in its initial, or S-1, segment. Transport from the blood into the tubular cell occurs by facilitated diffusion, driven by the electrochemical gradient for organic cations across the basolateral membrane. Upon entry, a substantial fraction of the cation (1/3 - 2/3) is actively transported into endosomal vesicles in exchange for intravesicular protons. A steep proton gradient is maintained between the vesicle's interior and the cytoplasm by a potent proton-ATPase. Sequestration may protect the cells by reducing the cytoplasmic content of potentially toxic agents during their excretion. Preliminary evidence also suggests that microtubule-dependent vesicular trafficking plays a direct role in transcellular flux of cationic drugs. At the luminal membrane, cationic drugs are transported into the tubular lumen via proton/organic cation antiport. In addition, larger, more lipophilic cations may be actively extruded via ATP-driven transport mediated by the multidrug resistance transporter. Together, the multiple steps of organic cation secretion control the excretory rate for cationic drugs and, thus, influence both residence time within the body and concentrations in plasma and at specific target sites.