First pass effect
The first pass effect describes the conversion of a drug during its first pass through the liver . The biochemical conversion (metabolization) that takes place in the process can result in an effective or ineffective metabolite . Some active ingredients only become effective through passage through the liver, others are inactivated to a certain extent. This effect is relevant for the drugs in question when they are administered in so-called peroral drug forms. These are all dosage forms that are swallowed, for example tablets , capsules , dragees and solutions intended for drinking .
A phenomenon with the opposite effect on bioavailability is the enterohepatic cycle of certain drugs and other substances.
Medicinal substances that are taken orally reach the stomach and then the small intestine after ingestion . They can be absorbed in both organs and thus enter the bloodstream . Since the stomach and small intestine are connected to the portal vein system ( vena portae hepatis ), they first enter the liver before they are distributed in the bloodstream in the rest of the body after passing through the liver and can thus reach their target sites. In the cells of the intestine and the liver, these substances are subject to biochemical reactions in which they can be broken down by enzymes or given certain chemical groups . These reactions are also known as metabolism , the reaction products are called metabolites. The aim of these reactions is to inactivate drugs that are foreign to the body and to increase their water solubility ( hydrophilicity ) in order to improve and accelerate their excretion. A pronounced first-pass effect means that an affected drug is largely metabolized or excreted before it reaches its site of action.
The rectum , on the other hand, is not fully connected to the portal vein system. It is surrounded by a venous plexus called the rectal venous plexus , which has drains into both the portal vein and vena cava systems . When the drug is administered rectally, for example via a suppository (suppository), the first-pass effect can thus be partially circumvented.
In the case of medicinal substances with a pronounced first-pass effect, their bioavailability and thus mostly their effect decreases , since a large part of the ingested active substance does not reach the site of action due to metabolism and excretion. However, it is also possible that the metabolites produced during passage through the liver also have an effect on the body. If this effect is desired, the actual drug is referred to as a so-called prodrug , i.e. a precursor to the actually active metabolite. However, undesirable effects from the metabolites of a drug are more common.
With some drugs, a first pass effect can only occur after a long period of regular use. This is the case if the regular intake stimulates an increased formation of the corresponding enzymes in the liver. This is known as enzyme induction . This reduces the effect of the drug in question when taken for a long time. The first-pass effect can also be desirable if, with topical application of a drug after its absorption, the effect and side effects on the entire organism are greatly reduced. A typical example of this is inhalation of the glucocorticoid budesonide .
There are essentially two ways of taking the first pass effect into account in the context of the therapeutic use of a drug if it has negative consequences for the effect. If the first pass effect only results in inactivation and excretion of the drug in question, this can be compensated for by increasing the dosage. This is possible because enzymatic processes and protein-mediated transport processes can be saturated. This means that the first pass effect is mostly dose-dependent. If, above a certain concentration, all active substance-eliminating systems are saturated, there is a significant increase in the systemically available amount of active substance. The dose at which this occurs is called the breakthrough dose . Exceeding the metabolic capacity of the liver can, however, have negative effects in the body, so that there are limits to increasing the dose.
In addition, it is not possible to increase the dose in the case of substances for which the first-pass effect leads to undesirable side effects due to the resulting metabolites. In these cases there may be the possibility of choosing a drug form without gastrointestinal passage, i.e. parenteral administration , for the same drug , for example a sublingual tablet , a suppository (suppository), a transdermal patch or an intravenous , intraperitoneal , subcutaneous one or intramuscular injection .
- Ernst Mutschler, Gerd Geisslinger, Heyo K. Kroemer, Monika Schäfer-Korting: drug effects. Textbook of pharmacology and toxicology. 8th edition. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2001, ISBN 3-8047-1763-2
- Eduard Burgis: Intensive course: General and special pharmacology. Elsevier, Urban & Fischer Verlag, 2008, ISBN 978-3-437-42613-1 , p. 15 ( limited preview in the Google book search).
- Peter Langguth: Biopharmacy. John Wiley & Sons, 2012, ISBN 978-3-527-66263-0 ( limited preview in Google Book Search).
- Andreas Hummel: Drug theory. Vincentz Network GmbH & Co KG, 2004, ISBN 978-3-878-70482-9 , p. 268 ( limited preview in the Google book search).