Drug Pathway and First-Pass Effect
When a patient takes a medication orally (per os), it is absorbed primarily in the small intestine (intestinum tenue). However, venous blood from there does not go directly into the general circulation. Via the portal vein (vena portae), all collected substances are directed to the liver (hepar). This is precisely where the first-pass effect through the liver unfolds.
Upon entering hepatocytes, molecules undergo presystemic elimination. The term "elimination" combines two processes that reduce the concentration of the active substance:
- Biotransformation: chemical conversion and inactivation of molecules by microsomal hepatic enzymes.
- Biliary excretion: physical removal of the unchanged substance or its metabolites into 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 overcame this barrier. Only a small fraction of drugs can bypass the portal vein by being absorbed via an alternative pathway — into the lymphatic bed.
Factors of Pre-hepatic Drug Loss
A drug begins to lose its active fraction even before encountering hepatic enzymes. The amount of substance that ultimately gets absorbed into the venous bed is influenced by aggressive factors of the gastrointestinal tract:
- Destruction in the stomach (gaster). The acidic environment (effect of hydrochloric acid) and proteolytic enzymes (such as pepsin) are capable of breaking down the dosage form and the active substance itself before absorption begins.
- Incomplete absorption. Characteristic of hydrophilic polar compounds, which have difficulty penetrating cell membranes.
- Metabolism in the intestinal wall. Enterocytes can alter the structure of the drug. A striking example is Levodopa, which is partially converted into dopamine by the enzyme dopa decarboxylase right inside 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 them from entering the blood.
Bioavailability and Dose Selection
Bioavailability is expressed as a percentage and indicates what fraction of the initial dose reached 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.
With intravenous administration, bioavailability is conventionally assumed to be 100%, as all tissue barriers are bypassed. With oral administration, this indicator is almost always lower due to presystemic elimination, which is why reference books usually provide data specifically for the per os route.
The clinical significance of the first-pass effect is enormous: drugs with a high degree of hepatic elimination have low bioavailability. This requires significant dose adjustment. A classic example is nitroglycerin. During passage through the liver, over 90% of this substance is degraded. To achieve the same therapeutic effect, the sublingual dose (under the tongue — bypassing the liver, sublinguim) is only 0.5 mg, while 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 drugs have the exact same active substance, dosage, dosage form, and route of administration (i.e., they are pharmaceutically equivalent), they may behave differently in the body due to differences in manufacturing technology and excipient composition.
For a copy of the original drug (generic) to be recognized as therapeutically equivalent, it must prove its bioequivalence (bioaequivalentia). This means that the generic and the original provide:
- Equal bioavailability (an equal amount of the substance enters the bloodstream);
- Equal rate of reaching maximum concentration ($C_{max}$) in blood plasma.
Briefly: answers to topical questions
Through which mechanisms are hydrophilic polar compounds absorbed across GI cell membranes?
Hydrophilic polar compounds are absorbed from the intestine with difficulty due to tight junctions and small intercellular spaces. The following pathways are possible:
- Filtration — passage through aqueous pores or intercellular spaces driven by a pressure gradient; for filtration, the molecule size must not exceed the pore diameter.
- Specific transport — carrier-mediated transport utilizing transport proteins when there is a chemical similarity to endogenous substrates.
What is the formula for calculating the absolute bioavailability of a medicinal product?
The absolute bioavailability of a medicinal product is calculated as the ratio of the area under the pharmacokinetic curve for oral administration to the area under the curve for intravenous administration.
Calculation formula: $F = \frac{AUC_{oral}}{AUC_{IV}} \times 100\%$
where:
- $F$ — bioavailability (expressed as a percentage);
- $AUC_{oral}$ — area under the concentration-time curve upon oral administration (per os);
- $AUC_{IV}$ — area under the curve upon intravenous administration (iniectio intravenosa), where bioavailability is assumed to be 100%.
Which routes of drug administration allow bypassing the first-pass hepatic effect?
Routes that allow bypassing the first-pass hepatic effect include:
- Sublingual administration — this route bypasses the liver.
- Parenteral routes of administration — intravenous, intramuscular, and subcutaneous administration; parenteral methods exclude the gastrointestinal tract.
- Lymphatic pathway — a portion of substances can be absorbed into the lymph, bypassing the portal vein.
Which specific enzymes carry out the biotransformation of drugs in hepatocytes?
Biotransformation of drugs in hepatocytes is carried out by two groups of enzymes:
- Microsomal enzymes — located in the membranes of the smooth endoplasmic reticulum. These include the cytochrome P450 system, which comprises cytochrome P450 and flavin-containing cytochrome P450 reductase; the complex often includes cytochrome b₅ and/or an iron-sulfur protein.
- Non-microsomal enzymes — located in the cytosol or mitochondria.
Class and exam questions
What Is the First-Pass Effect?
This is a process of presystemic elimination in which a significant portion of the drug absorbed in the intestine is degraded by liver enzymes before reaching the systemic circulation.
Why Are Oral Doses Often Higher Than Injection Doses?
Upon oral administration, part of the drug is destroyed by stomach acid, metabolized in the intestinal wall, and inactivated in the liver. To compensate for these losses, the dosage must be increased.
What Does It Mean If Two Drugs Are Bioequivalent?
This means that they have equal bioavailability and reach maximum blood concentration at the same rate, thus providing a comparable therapeutic effect.
What else to study on this topic
- Enterohepatic Circulation of Drugs
- The Role of P-glycoprotein in Pharmacokinetics
- Hepatic Microsomal Enzymes and Biotransformation
- Characteristics of Hydrophilic Compound Absorption
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