first pass effect

File:2138 Hepatic Portal Vein System.jpg

The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the site of action or systemic circulation.{{cite journal|last1=Rowland|first1=Malcolm|title=Influence of route of administration on drug availability|journal=Journal of Pharmaceutical Sciences|volume=61|issue=1|date=January 1972|pages=70–74|pmid=5019220|issn=0022-3549|doi=10.1002/jps.2600610111}}{{cite journal|last1=Pond|first1=Susan M.|last2=Tozer|first2=Thomas N.|title=First-Pass Elimination|journal=Clinical Pharmacokinetics|volume=9|issue=1|date=January 1984|pages=1–25|pmid=6362950|issn=0312-5963|doi=10.2165/00003088-198409010-00001|s2cid=28006040}} The effect is most associated with orally administered medications, but some drugs still undergo first-pass metabolism even when delivered via an alternate route (e.g., IV, IM, etc.).{{Citation |last=Carlin |first=Michelle G. |title=Pharmacology and Mechanism of Action of Drugs |date=2023-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780128236772000866 |encyclopedia=Encyclopedia of Forensic Sciences, Third Edition (Third Edition) |pages=144–154 |editor-last=Houck |editor-first=Max M. |access-date=2024-01-17 |place=Oxford |publisher=Elsevier |doi=10.1016/b978-0-12-823677-2.00086-6 |isbn=978-0-12-823678-9|url-access=subscription }} During this metabolism, drug is lost during the process of absorption which is generally related to the liver and gut wall. 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 buprenorphine, chlorpromazine, cimetidine, diazepam, ethanol (drinking alcohol), imipramine, insulin, lidocaine, midazolam, morphine, pethidine, propranolol, and tetrahydrocannabinol (THC).

First-pass metabolism is not to be confused with phase I metabolism, which is a separate process.

Factors

First-pass metabolism may occur in the liver (for propranolol, lidocaine, clomethiazole, and nitroglycerin) or in the gut (for benzylpenicillin and insulin).{{cite web|title=Understanding First Pass Metabolism|publisher=University of Nottingham|author=Bath-Hextall, Fiona|date=October 16, 2013|access-date=October 26, 2017|url=http://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/metabolism/01.html|archive-date=July 28, 2021|archive-url=https://web.archive.org/web/20210728110801/https://www.nottingham.ac.uk/nmp/sonet/rlos/bioproc/metabolism/01.html|url-status=live}} The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal lumen,{{Cite journal |last1=Ilett |first1=Kenneth F. |last2=Tee |first2=Lisa B. G. |last3=Reeves |first3=Philip T. |last4=Minchin |first4=Rodney F. |date=1990-01-01 |title=Mebolism of drugs and other xenobiotics in the gut lumen and wall |url=https://linkinghub.elsevier.com/retrieve/pii/0163725890900362 |journal=Pharmacology & Therapeutics |volume=46 |issue=1 |pages=67–93 |doi=10.1016/0163-7258(90)90036-2 |issn=0163-7258|url-access=subscription }} gastrointestinal wall enzymes,{{Cite journal |last1=Thummel |first1=Kenneth E. |last2=Kunze |first2=Kent L. |last3=Shen |first3=Danny D. |date=1997-09-15 |title=Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction |url=https://linkinghub.elsevier.com/retrieve/pii/S0169409X97000392 |journal=Advanced Drug Delivery Reviews |series=First-pass Metabolism and Its Impact on Oral Drug Delivery |volume=27 |issue=2 |pages=99–127 |doi=10.1016/S0169-409X(97)00039-2 |pmid=10837554 |issn=0169-409X|url-access=subscription }}{{Cite journal |last1=Drozdzik |first1=Marek |last2=Busch |first2=Diana |last3=Lapczuk |first3=Joanna |last4=Müller |first4=Janett |last5=Ostrowski |first5=Marek |last6=Kurzawski |first6=Mateusz |last7=Oswald |first7=Stefan |date=2018 |title=Protein Abundance of Clinically Relevant Drug-Metabolizing Enzymes in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens |url=https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.967 |journal=Clinical Pharmacology & Therapeutics |language=en |volume=104 |issue=3 |pages=515–524 |doi=10.1002/cpt.967 |pmid=29205295 |issn=1532-6535|url-access=subscription }}{{Cite journal |last1=Doherty |first1=Margaret M. |last2=Charman |first2=William N. |date=2002-04-01 |title=The Mucosa of the Small Intestine |url=https://link.springer.com/article/10.2165/00003088-200241040-00001 |journal=Clinical Pharmacokinetics |language=en |volume=41 |issue=4 |pages=235–253 |doi=10.2165/00003088-200241040-00001 |pmid=11978143 |issn=1179-1926|url-access=subscription }} bacterial enzymes and hepatic enzymes.{{Cite journal |last1=Bramer |first1=S. L. |last2=Au |first2=J. L. |last3=Wientjes |first3=M. G. |date=1993 |title=Gastrointestinal and hepatic first-pass elimination of 2',3'-dideoxyinosine in rats |url=https://pubmed.ncbi.nlm.nih.gov/8496819/ |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=265 |issue=2 |pages=731–738 |issn=0022-3565 |pmid=8496819}}

Hepatic first-pass

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 may greatly reduce the bioavailability of the drug.

An example of a drug where first-pass metabolism is a complication and disadvantage is in the antiviral drug remdesivir. 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 SARS-CoV-2).{{Cite journal|doi = 10.1021/acsmedchemlett.0c00316|title = Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment|year = 2020|last1 = Yan|first1 = Victoria C.|last2 = Muller|first2 = Florian L.|journal = ACS Medicinal Chemistry Letters|volume = 11|issue = 7|pages = 1361–1366|pmid = 32665809|pmc = 7315846}}{{cite web |title=Fact sheet for health care providers Emergency Use Authorization (EUA) of Veklury®(remdesivir) |website=Food and Drug Administration |url=https://www.fda.gov/media/137566/download |url-status=live |archive-url=https://web.archive.org/web/20200512234546/https://www.fda.gov/media/137566/download |archive-date=12 May 2020 |access-date=4 July 2024}} 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.

Drug design

In drug design, drug candidates may have good druglikeness but fail on first-pass metabolism because it is biochemically selective.{{Ambiguous|What is biochemically selective?|date=January 2024}} Physiologically based pharmacokinetic models (PBPK) are used to predict first-pass metabolism, although they require compound-specific adjustments due to variability in intestinal mucosal permeability and other factors.{{Cite journal |last1=Henriot |first1=Justine |last2=Dallmann |first2=André |last3=Dupuis |first3=François |last4=Perrier |first4=Jérémy |last5=Frechen |first5=Sebastian |date=2025 |title=PBPK modeling: What is the role of CYP3A4 expression in the gastrointestinal tract to accurately predict first-pass metabolism? |journal=CPT: Pharmacometrics & Systems Pharmacology |language=en |volume=14 |issue=1 |pages=130–141 |doi=10.1002/psp4.13249 |issn=2163-8306 |pmc=11706425 |pmid=39359052}}{{Cite journal |last1=Heikkinen |first1=Aki T. |last2=Baneyx |first2=Guillaume |last3=Caruso |first3=Antonello |last4=Parrott |first4=Neil |date=2012-09-29 |title=Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates – An evaluation and case study using GastroPlus™ |url=https://linkinghub.elsevier.com/retrieve/pii/S0928098712002576 |journal=European Journal of Pharmaceutical Sciences |volume=47 |issue=2 |pages=375–386 |doi=10.1016/j.ejps.2012.06.013 |pmid=22759901 |issn=0928-0987|url-access=subscription }}{{Cite journal |last1=Gertz |first1=Michael |last2=Harrison |first2=Anthony |last3=Houston |first3=J. Brian |last4=Galetin |first4=Aleksandra |date=2010 |title=Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data |url=https://linkinghub.elsevier.com/retrieve/pii/S0090955624024085 |journal=Drug Metabolism and Disposition |volume=38 |issue=7 |pages=1147–1158 |doi=10.1124/dmd.110.032649 |pmid=20368326 |issn=0090-9556|url-access=subscription }} Enzyme expression also varies between individuals, which may influence the efficiency of first-pass metabolism and thus the bioavailability of the drug.

Cytochromes P450, especially CYP3A4, play a crucial role in first-pass metabolism, affecting the bioavailability of drugs.{{Cite journal |last1=Jones |first1=Christopher R. |last2=Hatley |first2=Oliver J. D. |last3=Ungell |first3=Anna-Lena |last4=Hilgendorf |first4=Constanze |last5=Peters |first5=Sheila Annie |last6=Rostami-Hodjegan |first6=Amin |date=2016-05-01 |title=Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination |journal=The AAPS Journal |language=en |volume=18 |issue=3 |pages=589–604 |doi=10.1208/s12248-016-9889-y |issn=1550-7416 |pmc=5256607 |pmid=26964996}}

Mitigation

Converting a drug into a prodrug can help avoid first-pass metabolism, thereby improving its bioavailability.{{Citation |last1=Shakya |first1=Ashok K. |title=Chapter 8 - First-Pass Metabolism Considerations in Pharmaceutical Product Development |date=2018-01-01 |work=Dosage Form Design Considerations |pages=259–286 |editor-last=Tekade |editor-first=Rakesh K. |url=https://linkinghub.elsevier.com/retrieve/pii/B9780128144237000083 |series=Advances in Pharmaceutical Product Development and Research |publisher=Academic Press |doi=10.1016/b978-0-12-814423-7.00008-3 |isbn=978-0-12-814423-7 |last2=Al-Najjar |first2=Belal O. |last3=Deb |first3=Pran Kishore |last4=Naik |first4=Rajashri R. |last5=Tekade |first5=Rakesh K.|url-access=subscription }} In vitro models, such as the use of microfluidic chips that simulate the gut and liver, allow first-pass metabolism to be studied more accurately, facilitating the development of drugs with better absorption profiles.{{Cite journal |last1=Lee |first1=Bo-Eun |last2=Kim |first2=Do-Kyung |last3=Lee |first3=Hyunil |last4=Yoon |first4=Siyeong |last5=Park |first5=Sin-Hyung |last6=Lee |first6=Soonchul |last7=Yoo |first7=Jongman |date=2021 |title=Recapitulation of First Pass Metabolism Using 3D Printed Microfluidic Chip and Organoid |journal=Cells |language=en |volume=10 |issue=12 |pages=3301 |doi=10.3390/cells10123301 |doi-access=free |issn=2073-4409 |pmc=8699265 |pmid=34943808}}{{Cite journal |last1=Lee |first1=Dong Wook |last2=Ha |first2=Sang Keun |last3=Choi |first3=Inwook |last4=Sung |first4=Jong Hwan |date=2017-11-07 |title=3D gut-liver chip with a PK model for prediction of first-pass metabolism |url=https://link.springer.com/article/10.1007/s10544-017-0242-8 |journal=Biomedical Microdevices |language=en |volume=19 |issue=4 |pages=100 |doi=10.1007/s10544-017-0242-8 |issn=1572-8781|url-access=subscription }}{{Cite journal |last1=Choe |first1=Aerim |last2=Ha |first2=Sang Keun |last3=Choi |first3=Inwook |last4=Choi |first4=Nakwon |last5=Sung |first5=Jong Hwan |date=2017-01-10 |title=Microfluidic Gut-liver chip for reproducing the first pass metabolism |url=https://link.springer.com/article/10.1007/s10544-016-0143-2 |journal=Biomedical Microdevices |language=en |volume=19 |issue=1 |pages=4 |doi=10.1007/s10544-016-0143-2 |pmid=28074384 |issn=1572-8781|url-access=subscription }}

= Routes of administration =

Alternative routes of administration, such as insufflation, rectal administration,{{Cite journal |last1=de Boer |first1=A. G. |last2=Breimer |first2=D. D. |date=1997-11-10 |title=Hepatic first-pass effect and controlled drug delivery following rectal administration |url=https://linkinghub.elsevier.com/retrieve/pii/S0169409X97000744 |journal=Advanced Drug Delivery Reviews |series=Rectal Drug Delivery |volume=28 |issue=2 |pages=229–237 |doi=10.1016/S0169-409X(97)00074-4 |issn=0169-409X|url-access=subscription }}{{Cite book |title=Aulton's Pharmaceutics: the design and manufacture of medicines |date=2022 |publisher=Elsevier Health Sciences |isbn=978-0-7020-8154-5 |editor-last=Taylor |editor-first=Kevin |edition=6th |location=s.l. |page=5 |chapter=Design of dosage forms |editor-last2=Aulton |editor-first2=Michael E.}}{{Rp|page=5}} intravenous,{{Rp|page=|pages=4-5}} intramuscular, inhalational aerosol, transdermal, or sublingual, avoid or partially avoid the first pass effect because they allow drugs to be absorbed directly into the systemic circulation.{{Cite journal |last1=Mathias |first1=Neil R. |last2=Hussain |first2=Munir A. |year=2009 |title=Non-invasive Systemic Drug Delivery: Developability Considerations for Alternate Routes of Administration |url=https://linkinghub.elsevier.com/retrieve/pii/S0022354916303525 |journal=Journal of Pharmaceutical Sciences |volume=99 |issue=1 |pages=1–20 |doi=10.1002/jps.21793 |pmid=19499570 |issn=0022-3549|url-access=subscription }}

Drugs with high first pass effect typically have a considerably higher oral dose than sublingual or parenteral 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).

References

External links

National Library of Medicine, Toxicology Tutor II, [http://sis.nlm.nih.gov/enviro/toxtutor/Tox2/a32.htm Influence of Route of Exposure] {{Webarchive|url=https://web.archive.org/web/20100611064829/http://sis.nlm.nih.gov/enviro/toxtutor/Tox2/a32.htm |date=2010-06-11 }}
Herman TF, Santos C. First Pass Effect. 2022 Sep 24. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID 31869143.

Category:Pharmacokinetics

Category:Medicinal chemistry