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First Pass Effect

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Last Update: September 24, 2022.


The first pass effect is a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation. The first pass effect is often associated with the liver, as this is a major site of drug metabolism. However, the first pass effect can also occur in the lungs, vasculature, gastrointestinal tract, and other metabolically active tissues in the body. This effect can become augmented by various factors such as plasma protein concentrations, enzymatic activity, and gastrointestinal motility.[1][2][3][4] The extent to which a patient may experience the first pass effect varies from patient to patient, and this must also be taken into consideration when determining appropriate dosing.[5][1] If the first-pass effect is exceptionally prominent in a patient, the drug may require administration via a different route to bypass the first-pass effect.[6]

Issues of Concern

A significant issue of concern with the first pass effect is taking into account its variability among different individual patients. It is incredibly important that pharmacological dosing considers these natural variations in human metabolism to ensure patients remain within the therapeutic window of the appropriate drug.[5] Also, there have been noted differences in the first pass effect based on gender and age.[7][8]

Clinical Significance

The clinical significance of the first pass effect is crucial to the proper administration and maintenance of pharmacological therapy. Some drugs that undergo considerable first-pass metabolism include alprenolol, 5-fluorouracil, morphine, pentazocine, and mercaptopurine. When given orally, these drugs are quickly metabolized via the first-pass effect, requiring their oral dosages to be much larger than their intravenous dosages. The first pass effect also has an impact on peak drug concentrations, which may result in drug concentration peaks occurring much earlier than they would in a parenteral dose.[1][9]

It is critical to maintain proper serum concentrations of a drug that experiences the first-pass effect; this allows for the maintenance of a safe and effective dose of the drug. Research has shown that monitoring blood concentrations of drugs that experience the first-pass effect is the most viable way to maintain therapeutic concentrations of these drugs.[10] [Level 3]

Nursing, Allied Health, and Interprofessional Team Interventions

The interprofessional healthcare team, e.g., physicians, nurses, pharmacists, etc., needs to work together to ensure the safety and efficacy of pharmacotherapy. Importantly, the healthcare team needs to monitor for signs of adverse drug reactions. The pharmacist should verify the dosing and perform a drug interaction check. Nurses can monitor adverse events and make preliminary assessments of treatment effectiveness on subsequent visits. The application of basic pharmacokinetic concepts, e.g., the first pass effect, can ensure the appropriate drug route of administration and dosing of the patient.

Both nurses and pharmacists need to have an open communication line with the prescribing physician so they can report or discuss any concerns regarding pharmacotherapy. This type of interprofessional healthcare team communication is necessary to optimize patient outcomes with minimal adverse events. [Level 5]

Nursing, Allied Health, and Interprofessional Team Monitoring

When monitoring patients that are taking drugs that experience the first-pass effect, it is critical to monitor the blood concentrations of these drugs to ensure that the patients' serum drug concentrations remain within their therapeutic windows. Doing so will maximize the efficacy of treatment and patient safety.[10]

Review Questions


Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984 Jan-Feb;9(1):1-25. [PubMed: 6362950]
Doherty MM, Pang KS. First-pass effect: significance of the intestine for absorption and metabolism. Drug Chem Toxicol. 1997 Nov;20(4):329-44. [PubMed: 9433662]
Wang X, Zheng M, Liu J, Huang Z, Bai Y, Ren Z, Wang Z, Tian Y, Qiao Z, Liu W, Feng F. Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats. J Ethnopharmacol. 2017 Sep 14;209:175-183. [PubMed: 28755970]
Shen DD, Kunze KL, Thummel KE. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev. 1997 Sep 15;27(2-3):99-127. [PubMed: 10837554]
Tam YK. Individual variation in first-pass metabolism. Clin Pharmacokinet. 1993 Oct;25(4):300-28. [PubMed: 8261714]
Mattes RD, Shaw LM, Edling-Owens J, Engelman K, Elsohly MA. Bypassing the first-pass effect for the therapeutic use of cannabinoids. Pharmacol Biochem Behav. 1993 Mar;44(3):745-7. [PubMed: 8383856]
Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, Schaefer C, Lieber CS. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res. 2001 Apr;25(4):502-7. [PubMed: 11329488]
Wynne H. Drug metabolism and ageing. J Br Menopause Soc. 2005 Jun;11(2):51-6. [PubMed: 15970015]
Lalka D, Griffith RK, Cronenberger CL. The hepatic first-pass metabolism of problematic drugs. J Clin Pharmacol. 1993 Jul;33(7):657-69. [PubMed: 8366191]
Wargin WA, Sawchuk RJ, McBride JW, McCoy HG, Rylander ML. Variable first-pass elimination of propranolol following single and multiple oral doses in hypertensive patients. Eur J Drug Metab Pharmacokinet. 1982;7(3):183-9. [PubMed: 7173272]
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Bookshelf ID: NBK551679PMID: 31869143


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