First-Pass Effect

Lester Sultatos New Jersey Medical School, Newark, USA

ã 2007 Elsevier Inc. All rights reserved.

A first-pass effect is defined as a low systemic availability of the drug as a result of

significant metabolism. Although a first-pass effect can occur in a variety of tissues,
including the intestines Doherty and Pang (1997) and uterus De Ziegler et al (1997), it
is most often observed with the liver. Drug absorbed from the gastrointestinal tract
travels immediately to the liver through the hepatic portal vein. Hepatic first pass occurs
when drug absorbed from the gastrointestinal tract is metabolized by enzymes within the
liver to such an extent that most of the active agent does not exit the liver and, therefore,
does not reach the systemic circulation (Fig. 1).
Drugs that undergo a significant first-pass effect are also said to have a high hepatic
clearance Greenblatt (1993). Systemic availability is evaluated by comparing the areas
under the curves for the plasma concentration time curves following oral and intravenous
administration on two separate occasions in the same individual Greenblatt (1993). For a
drug that is completely absorbed from the gastrointestinal tract, the loss through hepatic
metabolism is signified by a decrease in the area under the curve following oral as
compared with intravenous administration. Significant intestinal drug metabolism, or
transport by p-glycoprotein, has similar effects on drug available. Reduced systemic
availability as a result of a first-pass effect can be overcome by increasing the dose or
by employing a different route of administration.
Reductions in hepatic clearance can have significant clinical consequences. Thus, a
decrease in the metabolism of a drug that typically undergoes hepatic first pass can result
in a substantial increase in peak plasma concentration and systemic availability. This may
necessitate a reduction in dose to avoid undesirable side effects or toxicities. Reduction in
hepatic drug metabolizing activity, or a reduction in hepatic blood flow, which can occur
as a result of aging, disease, or exposure to some drugs, can lower hepatic clearance
Greenblatt (1993), Somber et al (1993).

Other Information – Web Sites

http://www.merck.com/pubs/mmanual/section22/chapter298/298a.htm This is an open

access website that contains a discussion of absorption, distribution, biotransformation,
and excretion of drugs.

Fig. 1. Drug absorbed from the gastrointestinal tract travels immediately to the liver through the
hepatic portal vein.

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Journal Citations

Doherty, M.M., Pang, K.S., 1997. First-pass effect: Significance of the intestine for absorption and
metabolism. Drug Chem. Toxicol., 20(4), 329–344.
De Ziegler, D., Bulletti, C., Monstier, B., Jaaskelainen, A.S., 1997. The first uterine pass effect.
Ann. N. Y. Acad. Sci., 828, 291–299.
Greenblatt, D.J., 1993. Presystemic extraction: Mechanisms and consequences. J. Clin. Pharmacol., 33,
650–656.
Somber, J., Shroff, G., Khosla, S., Ehrenpreis, S., 1993. The clinical implications of first-pass metabolism:
Treatment strategies for the 1990s. J. Clin. Pharmacol., 33, 670–673.

Further Reading

Introduction, In: B. G. Katzung (Ed.), Basic and Clinical Pharmacology, Edition 8, McGraw-Hill, New York,
2001, pp. 1–8
Holford, N.H.G., Pharmacokinetics and Pharmacodynamics: Rationale Dosing & the Time Course of Drug
Action, In: B. G. Katzung (Ed.), Basic and Clinical Pharmacology, Edition 8, McGraw-Hill, New York, 2001,
pp. 35–50
Yagiela, J.A., Pharmacokinetics: the Absorption, Distribution, and Fate of Drugs, In: J. A. Yagiela,
F. A. Neidle and F. J. Dowd (Eds.), Pharmacology and Therapeutics for Dentistry, Edition 4, Mosby,
St. Louis, MO, 1998, pp. 15–41
Wilkinson, G.R., Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination, In:
J. G. Hardman and L. E. Limbird (Eds.), Goodman and Gilman’s The Pharmacological Basis of
Therapeutics, Edition 10, McGraw-Hill, New York, 2001, pp. 3–29