Drug Elimination VIII

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 . 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 degree
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 unprotonated)
form. This relationship is graphically
illustrated 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 (pKa = 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).