Illustration showing the hepatic portal vein system
Thefirst pass effect (FPE), also known asfirst-pass metabolism (FPM) orpresystemic metabolism, is a phenomenon ofdrug metabolism at a specific location in the body which leads to a reduction in theconcentration of the activedrug before it reaches the site of action or systemic circulation.[1][2] The effect is most associated withorally administeredmedications, 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 ofabsorption which is generally related to theliver andgut 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.
First-pass metabolism may occur in the liver (for propranolol, lidocaine,clomethiazole, and nitroglycerin) or in the gut (forbenzylpenicillin andinsulin).[4] The four primary systems that affect the first pass effect of a drug are theenzymes of thegastrointestinallumen,[5] gastrointestinal wall enzymes,[6][7][8] bacterial enzymes[5] and hepatic enzymes.[6][7][9]
After a drug is swallowed, it is absorbed by thedigestive system and enters thehepatic portal system. It is carried through theportal vein into theliver before it reaches the rest of the body. The livermetabolizes many drugs, sometimes to such an extent that only a small amount ofactive drug emerges from the liver to the rest of thecirculatory system. Thisfirst pass through the liver thus may greatly reduce thebioavailability of the drug.
An example of a drug where first-pass metabolism is a complication and disadvantage is in the antiviral drugremdesivir. 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 withSARS-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.
Indrug design, drug candidates may have gooddruglikeness but fail on first-pass metabolism because it is biochemicallyselective.[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]
Converting a drug into aprodrug can help avoid first-pass metabolism, thereby improving its bioavailability.[16] In vitro models, such as the use ofmicrofluidic 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.[17][18][19]
Drugs with high first pass effect typically have a considerably higher oral dose than sublingual orparenteral 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 andchlorpromazine).
^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.doi:10.1016/S0022-3565(25)38201-7.ISSN0022-3565.PMID8496819.
^abTaylor, 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.ISBN978-0-7020-8154-5.
