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<title>First pass effect</title>

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First pass effect

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</style><div role="note" class="hatnote navigation-not-searchable">Not to be confused with <a href="First_dose_effect" class="mw-redirect" title="First dose effect">First dose effect</a>.</div>

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The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of <a href="Drug_metabolism" title="Drug metabolism">drug metabolism</a> at a specific location in the body which leads to a reduction in the <a href="Concentration" title="Concentration">concentration</a> of the active <a href="Drug" title="Drug">drug</a> before it reaches the site of action or systemic circulation.<a href="#cite_note-Rowland1972-1">[1]</a><a href="#cite_note-PondTozer1984-2">[2]</a> The effect is most associated with <a href="Orally_administered" class="mw-redirect" title="Orally administered">orally administered</a> <a href="Medication" title="Medication">medications</a>, but some drugs still undergo first-pass metabolism even when delivered via an alternate route (e.g., <a href="Intravenous_therapy" title="Intravenous therapy">IV</a>, <a href="Intramuscular_injection" title="Intramuscular injection">IM</a>, etc.).<a href="#cite_note-3">[3]</a> During this metabolism, drug is lost during the process of <a href="Absorption_(pharmacology)" title="Absorption (pharmacology)">absorption</a> which is generally related to the <a href="Liver" title="Liver">liver</a> and <a href="Gut_wall" class="mw-redirect" title="Gut wall">gut wall</a>. The liver is the major site of first pass effect; however, it can also occur in the lungs, vasculature or other metabolically active tissues in the body.

Notable drugs that experience a significant first pass effect are <a href="Buprenorphine" title="Buprenorphine">buprenorphine</a>, <a href="Chlorpromazine" title="Chlorpromazine">chlorpromazine</a>, <a href="Cimetidine" title="Cimetidine">cimetidine</a>, <a href="Diazepam" title="Diazepam">diazepam</a>, <a href="Alcohol_(drug)" title="Alcohol (drug)">ethanol</a> (drinking alcohol), <a href="Imipramine" title="Imipramine">imipramine</a>, <a href="Insulin_(medication)" title="Insulin (medication)">insulin</a>, <a href="Lidocaine" title="Lidocaine">lidocaine</a>, <a href="Midazolam" title="Midazolam">midazolam</a>, <a href="Morphine" title="Morphine">morphine</a>, <a href="Pethidine" title="Pethidine">pethidine</a>, <a href="Propranolol" title="Propranolol">propranolol</a>, and <a href="Tetrahydrocannabinol" title="Tetrahydrocannabinol">tetrahydrocannabinol</a> (THC).

First-pass metabolism is not to be confused with <a href="Phase_I_metabolism" class="mw-redirect" title="Phase I metabolism">phase I metabolism</a>, which is a separate process.

<div class="mw-heading mw-heading2"><h2 id="Factors">Factors</h2></div>

First-pass metabolism may occur in the liver (for propranolol, lidocaine, <a href="Clomethiazole" title="Clomethiazole">clomethiazole</a>, and nitroglycerin) or in the gut (for <a href="Benzylpenicillin" title="Benzylpenicillin">benzylpenicillin</a> and <a href="Insulin" title="Insulin">insulin</a>).<a href="#cite_note-4">[4]</a> The four primary systems that affect the first pass effect of a drug are the <a href="Enzyme" title="Enzyme">enzymes</a> of the <a href="Gastrointestinal_tract" title="Gastrointestinal tract">gastrointestinal</a> <a href="Lumen_(anatomy)" title="Lumen (anatomy)">lumen</a>,<a href="#cite_note-:0-5">[5]</a> gastrointestinal wall enzymes,<a href="#cite_note-:1-6">[6]</a><a href="#cite_note-:2-7">[7]</a><a href="#cite_note-8">[8]</a> bacterial enzymes<a href="#cite_note-:0-5">[5]</a> and hepatic enzymes.<a href="#cite_note-:1-6">[6]</a><a href="#cite_note-:2-7">[7]</a><a href="#cite_note-9">[9]</a>

<div class="mw-heading mw-heading2"><h2 id="Hepatic_first-pass">Hepatic first-pass</h2></div>

After a drug is swallowed, it is absorbed by the <a href="Digestive_system" class="mw-redirect" title="Digestive system">digestive system</a> and enters the <a href="Hepatic_portal_system" title="Hepatic portal system">hepatic portal system</a>. It is carried through the <a href="Hepatic_portal_vein" class="mw-redirect" title="Hepatic portal vein">portal vein</a> into the <a href="Liver" title="Liver">liver</a> before it reaches the rest of the body. The liver <a href="Metabolism" title="Metabolism">metabolizes</a> many drugs, sometimes to such an extent that only a small amount of <a href="Active_pharmaceutical_ingredient" class="mw-redirect" title="Active pharmaceutical ingredient">active drug</a> emerges from the liver to the rest of the <a href="Circulatory_system" title="Circulatory system">circulatory system</a>. This first pass through the liver thus may greatly reduce the <a href="Bioavailability" title="Bioavailability">bioavailability</a> of the drug.

An example of a drug where first-pass metabolism is a complication and disadvantage is in the antiviral drug <a href="Remdesivir" title="Remdesivir">remdesivir</a>. Remdesivir cannot be administered orally because the entire dose would be trapped in the liver with little achieving systemic circulation or reaching target organs and cells (for example, cells infected with <a href="SARS-CoV-2" title="SARS-CoV-2">SARS-CoV-2</a>).<a href="#cite_note-10">[10]</a><a href="#cite_note-11">[11]</a> 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.

<div class="mw-heading mw-heading2"><h2 id="Drug_design">Drug design</h2></div>

In <a href="Drug_design" title="Drug design">drug design</a>, drug candidates may have good <a href="Druglikeness" title="Druglikeness">druglikeness</a> but fail on first-pass metabolism because it is biochemically <a href="Binding_selectivity" title="Binding selectivity">selective</a>. <a href="Physiologically_based_pharmacokinetic_modelling" title="Physiologically based pharmacokinetic modelling">Physiologically based pharmacokinetic models</a> (PBPK) are used to predict first-pass metabolism, although they require compound-specific adjustments due to variability in intestinal mucosal permeability and other factors.<a href="#cite_note-:3-12">[12]</a><a href="#cite_note-13">[13]</a><a href="#cite_note-:4-14">[14]</a> Enzyme expression also varies between individuals, which may influence the efficiency of first-pass metabolism and thus the bioavailability of the drug.<a href="#cite_note-:1-6">[6]</a>

<a href="Cytochrome_P450" title="Cytochrome P450">Cytochromes P450</a>, especially <a href="CYP3A4" title="CYP3A4">CYP3A4</a>, play a crucial role in first-pass metabolism, affecting the bioavailability of drugs.<a href="#cite_note-15">[15]</a><a href="#cite_note-:3-12">[12]</a><a href="#cite_note-:4-14">[14]</a>

<div class="mw-heading mw-heading2"><h2 id="Mitigation">Mitigation</h2></div>

Converting a drug into a <a href="Prodrug" title="Prodrug">prodrug</a> can help avoid first-pass metabolism, thereby improving its bioavailability.<a href="#cite_note-16">[16]</a> In vitro models, such as the use of <a href="Microfluidic_chips" class="mw-redirect" title="Microfluidic chips">microfluidic chips</a> that simulate the gut and liver, allow first-pass metabolism to be studied more accurately, facilitating the development of drugs with better absorption profiles.<a href="#cite_note-17">[17]</a><a href="#cite_note-18">[18]</a><a href="#cite_note-19">[19]</a>

<div class="mw-heading mw-heading3"><h3 id="Routes_of_administration">Routes of administration</h3></div>

Alternative <a href="Route_of_administration" title="Route of administration">routes of administration</a>, such as <a href="Insufflation_(medicine)" title="Insufflation (medicine)">insufflation</a>, <a href="Rectal_administration" title="Rectal administration">rectal administration</a>,<a href="#cite_note-20">[20]</a><a href="#cite_note-:5-21">[21]</a>: 5 <a href="Intravenous" class="mw-redirect" title="Intravenous">intravenous</a>,<a href="#cite_note-:5-21">[21]</a>: 4–5 <a href="Intramuscular" class="mw-redirect" title="Intramuscular">intramuscular</a>, <a href="Metered-dose_inhaler" title="Metered-dose inhaler">inhalational aerosol</a>, <a href="Transdermal_patch" title="Transdermal patch">transdermal</a>, or <a href="Sublingual" class="mw-redirect" title="Sublingual">sublingual</a>, avoid or partially avoid the first pass effect because they allow drugs to be absorbed directly into the <a href="Systemic_circulation" class="mw-redirect" title="Systemic circulation">systemic circulation</a>.<a href="#cite_note-22">[22]</a>

Drugs with high first pass effect typically have a considerably higher oral dose than sublingual or <a href="Parenteral" class="mw-redirect" title="Parenteral">parenteral</a> 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 <a href="Chlorpromazine" title="Chlorpromazine">chlorpromazine</a>).

<ul><li><a href="ADME" title="ADME">ADME</a>, an acronym in <a href="Pharmacokinetics" title="Pharmacokinetics">pharmacokinetics</a> and <a href="Pharmacology" title="Pharmacology">pharmacology</a> standing for absorption, distribution, metabolism, and excretion</li>

<li><a href="Biopharmaceutics_Classification_System" title="Biopharmaceutics Classification System">Biopharmaceutics Classification System</a></li>

<li><a href="Enteral_administration" title="Enteral administration">Enteral administration</a></li>

<li><a href="Partition_coefficient" title="Partition coefficient">Partition coefficient</a></li></ul>

<div class="mw-heading mw-heading2"><h2 id="References">References</h2></div>

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<div class="mw-heading mw-heading2"><h2 id="External_links">External links</h2></div>

<ul><li><a href="National_Library_of_Medicine" class="mw-redirect" title="National Library of Medicine">National Library of Medicine</a>, Toxicology Tutor II, <a rel="nofollow" class="external text" href="http://sis.nlm.nih.gov/enviro/toxtutor/Tox2/a32.htm">Influence of Route of Exposure</a> <a rel="nofollow" class="external text" href="https://web.archive.org/web/20100611064829/http://sis.nlm.nih.gov/enviro/toxtutor/Tox2/a32.htm">Archived</a> 2010-06-11 at the <a href="Wayback_Machine" title="Wayback Machine">Wayback Machine</a></li>

<li>Herman TF, Santos C. First Pass Effect. 2022 Sep 24. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID 31869143.</li></ul></div><div><div class="zim-footer">

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