First pass effect
Encyclopedia
The first-pass effect is a phenomenon of drug metabolism
whereby the concentration
of a drug
is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver
and gut wall. Notable drugs that experience a significant first-pass effect are imipramine
, morphine
, propranolol, buprenorphine
, diazepam
, midazolam
, demerol, cimetidine
, and lidocaine
.
After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein
into the liver
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
. This first pass through the liver thus greatly reduces the bioavailability
of the drug. Alternative routes of administration
like suppository
, intravenous, intramuscular, inhalational aerosol and sublingual
avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation
.
The four primary systems that affect the first pass effect of a drug are the enzymes 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.
The first pass effect can also be exploited for a beneficial effect. Some prodrug
s, for example codeine
(methylmorphine, inactive) are converted from an inactive form to the pharmacologically active form (morphine proper) by first pass metabolism (in this case, demethylation).
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
whereby the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
of a drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and gut wall. Notable drugs that experience a significant first-pass effect are imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, propranolol, buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...
, diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, midazolam
Midazolam
Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
, demerol, cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
, and lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
.
After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein
Hepatic portal vein
The hepatic portal vein is not a true vein, because it does not conduct blood directly to the heart. It is a vessel in the abdominal cavity that drains blood from the gastrointestinal tract and spleen to capillary beds in the liver...
into the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
before it reaches the rest of the body. The liver metabolizes
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
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
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
. This first pass through the liver thus greatly reduces the bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of the drug. Alternative routes of administration
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
like suppository
Suppository
A suppository is a drug delivery system that is inserted into the rectum , vagina or urethra , where it dissolves.They are used to deliver both systemically-acting and locally-acting medications....
, intravenous, intramuscular, inhalational aerosol and sublingual
Sublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...
.
The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
, gut wall enzymes, bacterial enzymes, and hepatic enzymes.
In drug design
Drug design
Drug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
, drug candidates may have good druglikeness
Druglikeness
Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. It is estimated from the molecular structure before the substance is even synthesized and tested...
but fail on first-pass metabolism, because it is biochemically selective.
The first pass effect can also be exploited for a beneficial effect. Some prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
s, for example codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
(methylmorphine, inactive) are converted from an inactive form to the pharmacologically active form (morphine proper) by first pass metabolism (in this case, demethylation).
See also
- ADMEADMEADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
, an acronym in pharmacokineticsPharmacokineticsPharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
and pharmacologyPharmacologyPharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
standing for absorption, distribution, metabolism, and excretion - Biopharmaceutics Classification SystemBiopharmaceutics Classification SystemThe Biopharmaceutics Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration . The fundamental basis for the BCS was established by Dr...
- DrugDrugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
- Partition coefficientPartition coefficientIn chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are...