The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of
drug metabolism whereby the
concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', ''number concentration'', ...
of a
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhala ...
, specifically when administered orally, is greatly reduced before it reaches the systemic circulation.
It is the fraction of drug lost during the process of absorption which is generally related to the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
and gut wall. Notable drugs that experience a significant first-pass effect are
buprenorphine,
chlorpromazine,
cimetidine
Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.
The development of longer-acting H2 r ...
,
diazepam,
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
(drinking alcohol),
imipramine,
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
,
lidocaine,
midazolam,
morphine
Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...
,
pethidine,
propranolol, and
tetrahydrocannabinol
Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
(THC).
First pass metabolism may occur in the liver (for propranolol, lidocaine,
clomethiazole, and NTG) or in the gut (for
benzylpenicillin and
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
).
After a drug is swallowed, it is absorbed by the
digestive system
The human digestive system consists of the gastrointestinal tract plus the accessory organs of digestion (the tongue, salivary glands, pancreas, liver, and gallbladder). Digestion involves the breakdown of food into smaller and smaller compone ...
and enters the
hepatic portal system
In human anatomy, the hepatic portal system is the system of veins comprising the hepatic portal vein and its tributaries. It is also called the portal venous system (although it is not the only example of a portal venous system) and splanchnic ...
. It is carried through the
portal vein
The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approx ...
into the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
before it reaches the rest of the body. The liver
metabolizes many drugs, sometimes to such an extent that only a small amount of
active drug emerges from the liver to the rest of the
circulatory system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. This ''first pass'' through the liver thus may greatly reduce the
bioavailability of the drug.
An example of a drug where first pass metabolism is a complication and disadvantage is the antiviral drug,
Remdesivir. Remdesivir cannot be orally administered because the entire dose would be trapped in the liver with little reaching the systemic circulation and reaching organs and cells affected by, for example,
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
.
[https://www.fda.gov/media/137566/download ] For this reason, Remdesivir is administered by IV infusion, bypassing the portal vein. However, significant hepatic extraction still occurs because of second pass metabolism, whereby a fraction of venous blood travels through the hepatic portal vein and hepatocytes.
The four primary systems that affect the first pass effect of a drug are the
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s of the
gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes.
In
drug design, drug candidates may have good
druglikeness but fail on first-pass metabolism because it is biochemically selective.
Alternative
routes of administration, such as
insufflation,
suppository,
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
,
intramuscular
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...
,
inhalational aerosol,
transdermal, or
sublingual
Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue.
The sublingual glands receive their primary ...
, avoid the first-pass effect because they allow drugs to be absorbed directly into the
systemic circulation
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, t ...
.
Drugs with high first pass effect typically have a considerably higher oral dose than sublingual or
parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
dose. There is marked individual variation in the oral dose due to differences in the extent of first pass metabolism, frequently among several other factors. Oral bioavailability of many vulnerable drugs appears to be increased in patients with compromised liver function. Bioavailability is also increased if another drug competing for first pass metabolism enzymes is given concurrently (e.g., propranolol and
chlorpromazine).
See also
*
ADME, an acronym in
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
and
pharmacology
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
standing for absorption, distribution, metabolism, and excretion
*
Biopharmaceutics Classification System
*
Drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhala ...
*
Enteral administration
*
Partition coefficient
References
External links
*
National Library of Medicine
The United States National Library of Medicine (NLM), operated by the United States federal government, is the world's largest medical library.
Located in Bethesda, Maryland, the NLM is an institute within the National Institutes of Health. Its ...
, ''Toxicology Tutor II''
Influence of Route of Exposure
Pharmacokinetics
Medicinal chemistry
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