The Kidney as Excretory Organ

Most drugs are eliminated in urine ei-ther chemically unchanged or as metab-olites. The kidney permits eliminationbecause the vascular wall structure inthe region of the glomerular capillaries allows unimpeded passage of bloodsolutes having molecular weights (MW)5000. Filtration diminishes progres-sively as MW increases from 5000 to70000 and ceases at MW 70000. Withfew exceptions, therapeutically useddrugs and their metabolites have muchsmaller molecular weights and can,therefore, undergo glomerular filtra-tion, i.e., pass from blood into primaryurine. Separating the capillary endothe-lium from the tubular epithelium, thebasal membrane consists of chargedglycoproteins and acts as a filtrationbarrier for high-molecular-weight sub-stances. The relative density of this bar-rier depends on the electrical charge ofmolecules that attempt to permeate it.Apart from glomerular filtration, drugs present in blood may passinto urine by active secretion. Certaincations and anions are secreted by theepithelium of the proximal tubules intothe tubular fluid via special, energy-consuming transport systems. Thesetransport systems have a limited capac-ity. When several substrates are presentsimultaneously, competition for thecarrier may occur.During passage down the renal tu-bule, urinary volume shrinks more than100-fold; accordingly, there is a corre-sponding concentration of filtered drugor drug metabolites. The resultingconcentration gradient between urineand interstitial fluid is preserved in thecase of drugs incapable of permeatingthe tubular epithelium. However, withlipophilic drugs the concentration gra-dient will favor reabsorption of the fil-tered molecules. In this case, reabsorp-tion is not based on an active processbut results instead from passive diffu-sion. Accordingly, for protonated sub-stances, the extent of reabsorption isdependent upon urinary pH or the degree of dissociation. The degree of disso-ciation varies as a function of the uri-nary pH and the pKa, which representsthe pH value at which half of the sub-stance exists in protonated (or unproto-nated) form. This relationship is graphi-cally illustrated with the example ofa protonated amine having a pKa of 7.0.In this case, at urinary pH 7.0, 50 % of theamine will be present in the protonated,hydrophilic,membrane-impermeantform (blue dots), whereas the other half,representing the uncharged amine(orange dots), can leave the tubular lu-men in accordance with the resultingconcentration gradient. If the pKa of anamine is higher (pKa = 7.5) or lower (pKa= 6.5), a correspondingly smaller orlarger proportion of the amine will bepresent in the uncharged, reabsorbableform. Lowering or raising urinary pH byhalf a pH unit would result in analogouschanges for an amine having a pKa of7.0.The same considerations hold foracidic molecules, with the importantdifference that alkalinization of theurine (increased pH) will promote thedeprotonization of -COOH groups andthus impede reabsorption. Intentionalalteration in urinary pH can be used inintoxications with proton-acceptor sub-stances in order to hasten elimination ofthe toxin (alkalinizationphenobarbi-tal; acidification amphetamine).