First pass effect

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Illustration showing the hepatic portal vein system 2138 Hepatic Portal Vein System.jpg
Illustration showing the hepatic portal vein system

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. [1] [2] 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.). [3] 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.

Contents

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). [4] The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal lumen, [5] gastrointestinal wall enzymes, [6] [7] [8] bacterial enzymes [5] and hepatic enzymes. [6] [7] [9]

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). [10] [11] 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 ] 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. [12] [13] [14] Enzyme expression also varies between individuals, which may influence the efficiency of first-pass metabolism and thus the bioavailability of the drug. [6]

Cytochromes P450, especially CYP3A4, play a crucial role in first-pass metabolism, affecting the bioavailability of drugs. [15] [12] [16]

Mitigation

Converting a drug into a prodrug can help avoid first-pass metabolism, thereby improving its bioavailability. [17] In vitro models, such as the use of microfluidic chips that simulate the gut and liver, allow for more accurate study of drug development.

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. [18] [19] [20]

Routes of administration

Alternative routes of administration, such as insufflation, rectal administration, [21] [22] intravenous, 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. [23]

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).

See also

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References

  1. ↑ Rowland, Malcolm (January 1972). "Influence of route of administration on drug availability". Journal of Pharmaceutical Sciences. 61 (1): 70–74. doi:10.1002/jps.2600610111. ISSN   0022-3549. PMID   5019220.
  2. ↑ Pond, Susan M.; Tozer, Thomas N. (January 1984). "First-Pass Elimination". Clinical Pharmacokinetics. 9 (1): 1–25. doi:10.2165/00003088-198409010-00001. ISSN   0312-5963. PMID   6362950. S2CID   28006040.
  3. ↑ Carlin, Michelle G. (2023-01-01), "Pharmacology and Mechanism of Action of Drugs", in Houck, Max M. (ed.), Encyclopedia of Forensic Sciences, Third Edition (Third Edition), Oxford: Elsevier, pp. 144–154, doi:10.1016/b978-0-12-823677-2.00086-6, ISBN   978-0-12-823678-9 , retrieved 2024-01-17
  4. ↑ Bath-Hextall, Fiona (October 16, 2013). "Understanding First Pass Metabolism". University of Nottingham. Archived from the original on July 28, 2021. Retrieved October 26, 2017.
  5. 1 2 Ilett, Kenneth F.; Tee, Lisa B. G.; Reeves, Philip T.; Minchin, Rodney F. (1990-01-01). "Mebolism of drugs and other xenobiotics in the gut lumen and wall". Pharmacology & Therapeutics. 46 (1): 67–93. doi:10.1016/0163-7258(90)90036-2. ISSN   0163-7258.
  6. 1 2 3 Thummel, Kenneth E.; Kunze, Kent L.; Shen, Danny D. (1997-09-15). "Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction". Advanced Drug Delivery Reviews. First-pass Metabolism and Its Impact on Oral Drug Delivery. 27 (2): 99–127. doi:10.1016/S0169-409X(97)00039-2. ISSN   0169-409X. PMID   10837554.
  7. 1 2 Drozdzik, Marek; Busch, Diana; Lapczuk, Joanna; Müller, Janett; Ostrowski, Marek; Kurzawski, Mateusz; Oswald, Stefan (2018). "Protein Abundance of Clinically Relevant Drug-Metabolizing Enzymes in the Human Liver and Intestine: A Comparative Analysis in Paired Tissue Specimens". Clinical Pharmacology & Therapeutics. 104 (3): 515–524. doi:10.1002/cpt.967. ISSN   1532-6535. PMID   29205295.
  8. ↑ Doherty, Margaret M.; Charman, William N. (2002-04-01). "The Mucosa of the Small Intestine". Clinical Pharmacokinetics. 41 (4): 235–253. doi:10.2165/00003088-200241040-00001. ISSN   1179-1926. PMID   11978143.
  9. ↑ Bramer, S. L.; Au, J. L.; Wientjes, M. G. (1993). "Gastrointestinal and hepatic first-pass elimination of 2',3'-dideoxyinosine in rats". The Journal of Pharmacology and Experimental Therapeutics. 265 (2): 731–738. ISSN   0022-3565. PMID   8496819.
  10. ↑ Yan, Victoria C.; Muller, Florian L. (2020). "Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment". ACS Medicinal Chemistry Letters. 11 (7): 1361–1366. doi:10.1021/acsmedchemlett.0c00316. PMC   7315846 . PMID   32665809.
  11. ↑ "Fact sheet for health care providers Emergency Use Authorization (EUA) of Veklury®(remdesivir)". Food and Drug Administration . Archived from the original on 12 May 2020. Retrieved 4 July 2024.
  12. 1 2 Henriot, Justine; Dallmann, André; Dupuis, François; Perrier, Jérémy; Frechen, Sebastian (2025). "PBPK modeling: What is the role of CYP3A4 expression in the gastrointestinal tract to accurately predict first-pass metabolism?". CPT: Pharmacometrics & Systems Pharmacology. 14 (1): 130–141. doi:10.1002/psp4.13249. ISSN   2163-8306. PMC   11706425 . PMID   39359052.
  13. ↑ Heikkinen, Aki T.; Baneyx, Guillaume; Caruso, Antonello; Parrott, Neil (2012-09-29). "Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates – An evaluation and case study using GastroPlus™". European Journal of Pharmaceutical Sciences. 47 (2): 375–386. doi:10.1016/j.ejps.2012.06.013. ISSN   0928-0987. PMID   22759901.
  14. ↑ Gertz, Michael; Harrison, Anthony; Houston, J. Brian; Galetin, Aleksandra (2010). "Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data". Drug Metabolism and Disposition. 38 (7): 1147–1158. doi:10.1124/dmd.110.032649. ISSN   0090-9556. PMID   20368326.
  15. ↑ Jones, Christopher R.; Hatley, Oliver J. D.; Ungell, Anna-Lena; Hilgendorf, Constanze; Peters, Sheila Annie; Rostami-Hodjegan, Amin (2016-05-01). "Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination". The AAPS Journal. 18 (3): 589–604. doi:10.1208/s12248-016-9889-y. ISSN   1550-7416. PMC   5256607 . PMID   26964996.
  16. ↑ Gertz, Michael; Harrison, Anthony; Houston, J. Brian; Galetin, Aleksandra (2010). "Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data". Drug Metabolism and Disposition. 38 (7): 1147–1158. doi:10.1124/dmd.110.032649. ISSN   0090-9556. PMID   20368326.
  17. ↑ Shakya, Ashok K.; Al-Najjar, Belal O.; Deb, Pran Kishore; Naik, Rajashri R.; Tekade, Rakesh K. (2018-01-01), Tekade, Rakesh K. (ed.), "Chapter 8 - First-Pass Metabolism Considerations in Pharmaceutical Product Development", Dosage Form Design Considerations, Advances in Pharmaceutical Product Development and Research, Academic Press, pp. 259–286, doi:10.1016/b978-0-12-814423-7.00008-3, ISBN   978-0-12-814423-7
  18. ↑ Lee, Bo-Eun; Kim, Do-Kyung; Lee, Hyunil; Yoon, Siyeong; Park, Sin-Hyung; Lee, Soonchul; Yoo, Jongman (2021). "Recapitulation of First Pass Metabolism Using 3D Printed Microfluidic Chip and Organoid". Cells. 10 (12): 3301. doi: 10.3390/cells10123301 . ISSN   2073-4409. PMC   8699265 . PMID   34943808.
  19. ↑ Lee, Dong Wook; Ha, Sang Keun; Choi, Inwook; Sung, Jong Hwan (2017-11-07). "3D gut-liver chip with a PK model for prediction of first-pass metabolism". Biomedical Microdevices. 19 (4): 100. doi:10.1007/s10544-017-0242-8. ISSN   1572-8781.
  20. ↑ Choe, Aerim; Ha, Sang Keun; Choi, Inwook; Choi, Nakwon; Sung, Jong Hwan (2017-01-10). "Microfluidic Gut-liver chip for reproducing the first pass metabolism". Biomedical Microdevices. 19 (1): 4. doi:10.1007/s10544-016-0143-2. ISSN   1572-8781. PMID   28074384.
  21. ↑ de Boer, A. G.; Breimer, D. D. (1997-11-10). "Hepatic first-pass effect and controlled drug delivery following rectal administration". Advanced Drug Delivery Reviews. Rectal Drug Delivery. 28 (2): 229–237. doi:10.1016/S0169-409X(97)00074-4. ISSN   0169-409X.
  22. ↑ Taylor, Kevin; Aulton, Michael E., eds. (2022). "Design of dosage forms". Aulton's Pharmaceutics: the design and manufacture of medicines (6th ed.). s.l.: Elsevier Health Sciences. p. 5. ISBN   978-0-7020-8154-5.
  23. ↑ Mathias, Neil R.; Hussain, Munir A. (2009). "Non-invasive Systemic Drug Delivery: Developability Considerations for Alternate Routes of Administration". Journal of Pharmaceutical Sciences. 99 (1): 1–20. doi:10.1002/jps.21793. ISSN   0022-3549. PMID   19499570.
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