Ho I

'Cd so3h

Active moiety of bisacodyl


B. Conjugation reactions

The Kidney as Excretory Organ

Most drugs are eliminated in urine either chemically unchanged or as metabolites. The kidney permits elimination because the vascular wall structure in the region of the glomerular capillaries (B) allows unimpeded passage of blood solutes having molecular weights (MW) < 5000. Filtration diminishes progressively as MW increases from 5000 to 70000 and ceases at MW > 70000. With few exceptions, therapeutically used drugs and their metabolites have much smaller molecular weights and can, therefore, undergo glomerular filtration, i.e., pass from blood into primary urine. Separating the capillary endothe-lium from the tubular epithelium, the basal membrane consists of charged glycoproteins and acts as a filtration barrier for high-molecular-weight substances. The relative density of this barrier depends on the electrical charge of molecules that attempt to permeate it.

Apart from glomerular filtration (B), drugs present in blood may pass into urine by active secretion. Certain cations and anions are secreted by the epithelium of the proximal tubules into the tubular fluid via special, energy-consuming transport systems. These transport systems have a limited capacity. When several substrates are present simultaneously, competition for the carrier may occur (see p. 268).

During passage down the renal tubule, urinary volume shrinks more than 100-fold; accordingly, there is a corresponding concentration of filtered drug or drug metabolites (A). The resulting concentration gradient between urine and interstitial fluid is preserved in the case of drugs incapable of permeating the tubular epithelium. However, with lipophilic drugs the concentration gradient will favor reabsorption of the filtered molecules. In this case, reabsorption is not based on an active process but results instead from passive diffusion. Accordingly, for protonated substances, the extent of reabsorption is dependent upon urinary pH or the de-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.

gree of dissociation. The degree of dissociation varies as a function of the urinary pH and the pKa, which represents the pH value at which half of the substance exists in protonated (or unproto-nated) form. This relationship is graphically illustrated (D) with the example of a protonated amine having a pKa of 7.0. In this case, at urinary pH 7.0, 50 % of the amine will be present in the protonated, hydrophilic, membrane-impermeant form (blue dots), whereas the other half, representing the uncharged amine (orange dots), can leave the tubular lumen in accordance with the resulting concentration gradient. If the pKa of an amine is higher (pi = 7.5) or lower (pKa = 6.5), a correspondingly smaller or larger proportion of the amine will be present in the uncharged, reabsorbable form. Lowering or raising urinary pH by half a pH unit would result in analogous changes for an amine having a pKa of 7.0.

The same considerations hold for acidic molecules, with the important difference that alkalinization of the urine (increased pH) will promote the deprotonization of -COOH groups and thus impede reabsorption. Intentional alteration in urinary pH can be used in intoxications with proton-acceptor substances in order to hasten elimination of the toxin (alkalinization ^ phenobarbital; acidification ^ amphetamine).

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