Drug Route and the First-Pass Effect
When a patient takes a drug orally (per os), it is absorbed primarily in the small intestine (intestinum tenue). However, venous blood from this region does not flow directly into the general circulation. Via the portal vein (vena portae), all absorbed substances are directed to the liver (hepar). This is where the first-pass effect through the liver takes place.
Upon entering hepatocytes, drug molecules undergo presystemic elimination. The term "elimination" encompasses two processes that reduce the active substance concentration:
- Biotransformation: Chemical alteration and inactivation of molecules by hepatic microsomal enzymes.
- Biliary excretion: Physical elimination of the unchanged drug or its metabolites into the bile (bilis), from where they return to the intestinal lumen (excreted in feces or participating in enterohepatic circulation).
Systemic circulation is reached only by those molecules that successfully overcome this barrier. Only a small fraction of drugs bypasses the portal vein by being absorbed via an alternative route—the lymphatic system.
Factors Causing Pre-Hepatic Drug Loss
A drug begins to lose its active fraction even before encountering hepatic enzymes. The amount of substance that ultimately enters the venous system is affected by hostile factors in the gastrointestinal tract:
- Gastric degradation (gaster). The acidic environment (hydrochloric acid) and proteolytic enzymes (such as pepsin) can break down the drug formulation and the active substance itself prior to absorption.
- Incomplete absorption. This is characteristic of hydrophilic polar compounds that cross cell membranes poorly.
- Intestinal wall metabolism. Enterocytes can alter drug structure. A prime example is Levodopa, which is partially converted to dopamine by dopa decarboxylase within the intestinal wall.
- Active transport (efflux). The transport protein P-glycoprotein literally "pumps" captured drug molecules out of enterocytes back into the intestinal lumen, preventing their entry into the blood.
Bioavailability and Dose Selection
Bioavailability is expressed as a percentage and indicates the fraction of the original dose that reaches the systemic circulation unchanged. In pharmacokinetics, it is generally accepted that there is a direct correlation between the concentration of a substance in the systemic circulation and its amount in target tissues.
Following intravenous administration, bioavailability is considered to be 100% because all tissue barriers are bypassed. Following oral administration, this value is almost always lower due to presystemic elimination, which is why reference data typically highlights the per os route.
Clinical significance of the first-pass effect is immense: drugs with a high degree of hepatic elimination have low bioavailability. This requires significant dose adjustments. A classic example is nitroglycerin. Over 90% of this substance is degraded during its first pass through the liver. To achieve the same therapeutic effect, the sublingual dose (under the tongue—bypassing the liver, sublingual) is only 0.5 mg, whereas the oral dose is 6.4 mg.
Pharmaceutical Aspects: From Release to Generics
Bioavailability depends not only on physiology but also on the completeness of active substance release from the tablet or capsule. Even if two products contain the exact same active substance, dosage, formulation, and route of administration (i.e., they are pharmaceutically equivalent), they may behave differently in the body due to variations in manufacturing technology and excipient composition.
For a copy of an original drug (generic) to be considered therapeutically equivalent, it must prove its bioequivalence (bioaequivalentia). This means that the generic and the reference drug provide:
- Equal bioavailability (an equal amount of substance reaches the bloodstream);
- An equal rate of maximum plasma concentration ($C_{max}$) attainment.