Pharmacokinetics – Part 2: Lipophilic and Hydrophilic drugs

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.

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