The medical profession refers to a biochemical metabolization process in the first liver passage as the first-pass effect, which deforms drugs taken perorally into so-called metabolites and thus either attenuates or activates their efficacy. The intensity of metabolization in the liver is directly related to personal liver functions and thus may differ from patient to patient. Especially in drug development, the first-pass effect plays a role because it is indispensably related to drug bioavailability.
What is the first-pass effect?
During the first passage of the liver, a drug undergoes biochemical conversion. How extreme this conversion is operated is related to the patient’s personal liver function. During the first passage of the liver, a drug is biochemically transformed. How extreme this transformation is operated depends on the personal liver function of the patient. The biochemical conversion process itself is also referred to by physicians as metabolization. Metabolization in the first passage of the liver is referred to medically as the first-pass effect and results in an intermediate product that has little to do with the actual drug. Either metabolization eliminates the efficacy of a drug, or it produces an effective product first, as in the case of peroral drugs developed with the first-pass effect in mind. Thus, while some drugs lose efficacy due to the first-pass effect, others are first activated by metabolization. In direct relation to this, pharmacokinetics understands the term first-pass effect to mean the amount of extract of a drug after its first passage through the liver.
Function, effect, and targets
The first-pass effect plays a role primarily for peroral drugs, that is, all drugs for swallowing. Tablets, coated tablets, and capsules fall under this category, as do drug solutions for drinking. After peroral ingestion, the drug enters the stomach, from where it moves on to the small intestine. In both the stomach and the small intestine, the drug begins to be absorbed so that it can enter the bloodstream and exert its effect. However, the stomach and small intestine are both connected to the so-called portal vein system, which means that drugs first reach the liver as part of this process. Only after passing through the liver passage do they enter the rest of the body with the blood and distribute themselves there to reach the site of their intended effect. Biochemical reactions such as the first-pass effect occur during both intestinal and hepatic passage. The enzymes of drugs taken perorally are thus cleaved and assigned to chemical groups. These metabolizations produce metabolites as reaction products, and the body generally attempts to deactivate the exogenous drug. As a rule, the water solubility of exogenous substances also increases in the course of metabolization, since the organism wants to eliminate the foreign substances as quickly as possible. Thus, if there is an extreme first-pass effect, the drug in question never reaches its site of action because it is excreted long beforehand. This reduces the bioavailability and general efficacy of the drug. On the other hand, so-called prodrugs take advantage of the first-pass effect because they are drugs that correspond to precursors of an effective metabolite. This means that only when they are metabolized in the liver do they become effective substances against a specific complaint. The involvement of the first-pass effect generally plays a special role in patients with liver disease. The desired form of metabolization is particularly relevant, again, for the topical application of drugs, where, after absorption, side effects on the whole organism can thus also be significantly reduced.
Risks, side effects, and hazards
Except in the case of prodrugs, the first-pass effect is usually an undesirable side effect of peroral drugs. Several approaches can be taken to avoid this side effect. For example, the rectum is not connected to the portal system. For this reason, suppositories can be used to circumvent the first-pass effect, for example.Other options for drug delivery independent of gastrointestinal passage are transdermal patches or intravenous and intramuscular injections. Ultimately, all parenteral, sublingual and buccal drug administrations are suitable for bypassing the liver passage. To the extent that this is within the realm of possibility without increased risks, however, increasing the dosage can also restore the efficacy of the peroral drug. Indeed, enzymatic processes and protein-mediated transport processes can be saturated in this way, so that the first-pass effect is almost always linked to a specific dose of the agent in question. At a certain dosage, all processes that weaken the active ingredient are saturated, and higher quantities of the active ingredient are automatically available to the respective system. The saturating concentration of the respective drug is also called the breakthrough dose. However, the dosage cannot be increased at will, since any overstepping of the liver’s internal metabolization capacity has negative consequences. A special feature of the metabolization process in the liver is its individuality. The first-pass effect thus varies from one person to another and is directly related to their liver functions. Accordingly, the breakthrough dose for a given drug also varies with the patient and their liver qualities. However, in patients who do not initially show a significant first-pass effect for a given drug at a given dosage, metabolization may still occur after some time. For example, if certain enzymes build up more in the liver as a result of taking the drug, then this enzyme induction may also decrease the efficacy of the drug with continued use.
