Fig. 34.6 illustrates the mechanism of organic cation (OC+) transport across the proximal tubule. Organic cations, including xenobiotics such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin, and many important monoamine neurotransmitters including dopamine, epinephrine, histamine, and norepinephrine are secreted by the proximal tubule. Organic cations are taken up into the cell across the basolateral membrane, primarily by the organic cation transporter 2 (OCT2). Uptake of organic cations is driven by the magnitude of the cell-negative potential difference across the basolateral membrane. Organic cation transport across the luminal membrane into the tubular fluid, which is the rate-limiting step in secretion, is mediated primarily by electroneutral multidrug and toxin extrusion transporters (MATEs) and MDR1 (also known as P-glycoprotein), which requires ATP for its operation. These transport mechanisms are nonspecific, and several organic cations usually compete for secretion via a given transport pathway.
Henle’s loop reabsorbs approximately 25% of the filtered NaCl and 15% of the filtered water. Reabsorption of NaCl
Because many organic anions compete for the same secretory pathways, elevated plasma levels of one transported anion often inhibit secretion of the others. For example, infusing p-aminohippuric acid (PAH) can reduce secretion of penicillin by the proximal tubule. Because the kidneys are responsible for eliminating penicillin, infusion of PAH into individuals receiving penicillin reduces penicillin excretion and thereby extends its biological half-life. In World War II, when penicillin was in short supply, hippurates were given with penicillin to extend its therapeutic effect. Similar competition is observed for organic cation secretion by the proximal tubule, and elevated plasma levels of one transported cation species can inhibit secretion of the other competing cations. For example, the histamine H2antagonist cimetidine used to treat gastric ulcers is secreted via organic cation transport mechanisms in the proximal tubule. If cimetidine is given to patients receiving procainamide (a drug used to treat cardiac arrhythmias), cimetidine reduces urinary excretion of procainamide (also an organic cation) by direct competition for a common secretory pathway. As a consequence, coadministration of cationic drugs competing for the same pathway can increase the plasma concentration of both drugs to levels much higher than those observed when the drugs are given alone. This effect can lead to drug toxicity.
•Fig. 34.7 Transport mechanisms for NaCl reabsorption in the thick ascending limb of the loop of Henle. The positive voltage in the lumen plays a major role in driving the passive paracellular reabsorption of cations. Because the apical membrane is conductive primarily to K+ , the apical membrane voltage is more negative than the basolateral membrane voltage, which is conductive to K+ and Cl− , thereby resulting in a lumen positive transepithelial potential. Mutations in the apical membrane K+ channel (ROMK), the apical membrane 1Na+/1K+/2Cl− symporter (NKCC2), or the basolateral Cl− channel (ClCNKB) cause Bartter syndrome (see the clinical box on Bartter syndrome). CA, carbonic anhydrase.
in the loop of Henle occurs in both the thin and thick ascending limbs, whereas the descending thin limb does not reabsorb NaCl. In contrast, water reabsorption mediated by AQP1 water channels is exclusively restricted to the descending thin limb, whereas the ascending limb is impermeable to water. In addition, divalent cations (e.g., Ca++ and Mg++) and HCO3 − are also reabsorbed in the loop of Henle (see for more details).