Pharmacokinetics: Lipophilic and hydrophilic drugs
Most drugs don’t use specialized transport systems of the body but instead diffuse through
the cell membrane.
To do so, a drug must be sufficiently lipophilic and, therefore, uncharged and nonpolar.
It dissolves in nonpolar liquids such as oil according to the “like dissolves like”
principle.
Therefore, such drugs are also literally termed “fat-loving”.
In contrast, polar or even charged substances dissolve well in polar solvents and are called
hydrophilic or “water-loving”.
Since biomembranes are composed of fatty acids, they represent a lipophilic barrier through
which hydrophilic molecules are unable to diffuse.
As a rule of thumb, drugs in their active form are usually lipophilic.
Whether a drug is lipophilic or hydrophilic has a great effect on its pharmacokinetic
properties, especially regarding its distribution, metabolism, and excretion:
If a hydrophilic drug is present in the circulation, it doesn’t diffuse through the cell membrane
and is, therefore, poorly absorbed by the surrounding tissue.
Instead, hydrophilic substances are excreted rapidly from the body.
For example, the renal reabsorption of hydrophilic drugs from primary urine is significantly
slower compared to lipophilic substances.
In contrast, a lipophilic drug can pass easily into the surrounding tissue.
The stronger the blood supply to an organ or tissue, the greater the amount of drug
taken into the organ.
At the same time, lipophilic drugs are excreted somewhat poorly from the body because they
can be largely reabsorbed in the kidney as well as the enterohepatic circulation.
Accordingly, such substances are metabolized in the liver, subsequently excreted into the
bile, and eliminated from the body.
Of course, such a conversion, also termed metabolism or biotransformation, can occur
with hydrophilic drugs as well.
Orally administered drugs are absorbed enterally into the portal circulation and transported
to the liver via the bloodstream.
Passing through the liver, the drugs are partially metabolized, which can greatly reduce the
maximum plasma concentration of a drug.
This process is termed the first-pass effect.
To avoid the first-pass effect, drugs should be administered in a different way, for example,
rectally instead of orally.
Venous drainage separates at the rectum with the upper part flowing via the superior rectal
vein to the portal vein, whereas the lower part flows via the inferior vena cava directly
to the heart.
Therefore, drugs absorbed in the rectum can enter directly into the systemic circulation.
But sometimes, the initial metabolism of a drug is desired.
This is the case, for example, if a prodrug is administered that needs to be transformed
into its pharmacologically active form.
As part of biotransformation, drug molecules in the liver are either conjugated and excreted
via the bowel, or are converted into a less lipophilic form, which is eliminated by the
kidneys.
If the modification process is slow, a major portion of the drug remains in the systemic
circulation and can be further absorbed by the tissue.
If drug conversion is rapid, the drug is excreted rapidly and poorly absorbed by the tissue,
similar to hydrophilic drugs.
Drug metabolism rates are important for physicians because it’s decisive in determining the
right dosage.
One should, however, consider that any metabolism rate differs both individually and depends
on age.
Because metabolism slows down with age, older patients usually require smaller drug amounts.
In addition, drug metabolism can be affected pathologically or through use of other drugs.
In liver disease, for example, drugs can no longer be rapidly converted.
Let’s get back to drug distribution in the body again.
It can also influence the effect of a drug.
Let’s use an anesthetic as an example.
To unfold its psychoactive effects, an intravenously administered anesthetic needs to cross the
blood-brain barrier.
As a reminder: The blood-brain barrier is a three-layered protective barrier that prevents
the uncontrolled entry of certain substances from the bloodstream into the brain.
The blood-brain barrier can only be crossed by highly lipophilic substances.
After passing through the blood-brain barrier, the anesthetic reaches its site of action
to produce its desired effect.
However, the lipophilic properties of an anesthetic also lead to another special attribute: it
can accumulate in adipose tissue.
The anesthetic passes from plasma into adipose tissue until concentrations are equal.
If plasma levels decrease as a result of another elimination process, the drug temporarily
stored in the adipose tissue diffuses back into the blood.
So in general, the more adipose tissue in the body, the greater the drug amount redistributed
or temporarily stored.
Therefore, drug distribution in the body should be especially taken into account in overweight
patients.