Drug Elimination IX

Elimination of Lipophilic and
Hydrophilic Substances
The terms lipophilic and hydrophilic
(or hydro- and lipophobic) refer to the
solubility of substances in media of low
and high polarity, respectively. Blood
plasma, interstitial fluid, and cytosol are
highly polar aqueous media, whereas
lipids — at least in the interior of the lipid
bilayer membrane — and fat constitute
apolar media. Most polar substances
are readily dissolved in aqueous media
(i.e., are hydrophilic) and lipophilic
ones in apolar media. A hydrophilic
drug, on reaching the bloodstream,
probably after a partial, slow absorption
(not illustrated), passes through the liver
unchanged, because it either cannot,
or will only slowly, permeate the lipid
barrier of the hepatocyte membrane
and thus will fail to gain access to hepatic
biotransforming enzymes. The unchanged
drug reaches the arterial blood
and the kidneys, where it is filtered.
With hydrophilic drugs, there is little
binding to plasma proteins (protein
binding increases as a function of lipophilicity),
hence the entire amount
present in plasma is available for glomerular
filtration. A hydrophilic drug is
not subject to tubular reabsorption and
appears in the urine. Hydrophilic drugs
undergo rapid elimination.
If a lipophilic drug, because of its
chemical nature, cannot be converted
into a polar product, despite having access
to all cells, including metabolically
active liver cells, it is likely to be retained
in the organism. The portion filtered
during glomerular passage will be
reabsorbed from the tubules. Reabsorption
will be nearly complete, because
the free concentration of a lipophilic
drug in plasma is low (lipophilic substances
are usually largely proteinbound).
The situation portrayed for a
lipophilic non-metabolizable drug
would seem undesirable because pharmacotherapeutic
measures once initiated
would be virtually irreversible (poor
control over blood concentration).