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First-Pass Elimination Basic Concepts and Clinical Consequences

Clinical Pharmacokinetics volume 9, pages 1–25 (1984)Cite this article

Summary

First-pass elimination takes place when a drug is metabolised between its site of administration and the site of sampling for measurement of drug concentration. Clinically, first-pass metabolism is important when the fraction of the dose administered that escapes metabolism is small and variable. The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally, but other potential sites are the gastrointestinal tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken. Bioavailability, defined as the ratio of the areas under the blood concentration-time curves, after extra- and intravascular drug administration (corrected for dosage if necessary), is often used as a measure of the extent of first-pass metabolism. When several sites of first-pass metabolism are in series, the bioavailability is the product of the fractions of drug entering the tissue that escape loss at each site.

The extent of first-pass metabolism in the liver and intestinal wall depends on a number of physiological factors. The major factors are enzyme activity, plasma protein and blood cell binding, and gastrointestinal motility. Models that describe the dependence of bioavailability on changes in these physiological variables have been developed for drugs subject to first-pass metabolism only in the liver. Two that have been applied widely are the ‘well-stirred’ and ‘parallel tube’ models. Discrimination between the 2 models may be performed under linear conditions in which all pharmacokinetic parameters are independent of concentration and time. The predictions of the models are similar when bioavailability is large but differ dramatically when bioavailability is small. The ‘parallel tube’ model always predicts a much greater change in bioavailability than the ‘well-stirred’ model for a given change in drug-metabolising enzyme activity, blood flow, or fraction of drug unbound.

Many clinically important drugs undergo considerable first-pass metabolism after an oral dose. Drugs in this category include alprenolol, amitriptyline, dihydroergotamine, 5-fluorouracil, hydralazine, isoprenaline (isoproterenol), lignocaine (lidocaine), lorcainide, pethidine (meperidine), mercaptopurine, metoprolol, morphine, neostigmine, nifedipine, pentazocine and propranolol. One major therapeutic implication of extensive first-pass metabolism is that much larger oral doses than intravenous doses are required to achieve equivalent plasma concentrations. For some drugs, extensive first-pass metabolism precludes their use as oral agents (e.g. lignocaine, naloxone and glyceryl trinitrate). Inhalation or buccal, rectal or transdermal administration may, in part, obviate the problems of extensive first-pass metabolism of an oral dose.

Drugs that undergo extensive first-pass metabolism may produce different plasma metabolite concentration-time profiles after oral and parenteral administration. After an oral dose, the concentration of the metabolite may reach a peak earlier than after a parenteral dose. Sometimes, metabolites have only been detected in plasma after an oral dose. Drugs in this category include alprenolol, amitriptyline, lorcainide, pethidine, nifedipine and propranolol. Although the plasma concentration-time profiles of metabolites may differ after oral and parenteral doses, the fraction of a dose eventually converted to a metabolite should be the same after each route of administration provided that the ingested drug is completely absorbed, is eliminated solely by metabolism in the liver, and has linear kinetics. Otherwise, the fraction of a dose administered that is converted to a metabolite may vary with route of administration (e.g. with isoprenaline and salbutamol). Variation in the concentration ratios between parent drug and metabolite may produce route-dependent differences in pharmacological and toxicological responses to a given concentration of the parent drug (e.g. with encainide, lorcainide, quinidine and verapamil).

Drugs that undergo extensive first-pass elimination exhibit pronounced interindividual variation in plasma concentrations or drug concentration-time curves after oral administration. This variation, often reflected in variability in drug response, poses one of the major problems in the clinical use of these drugs. Variability in first-pass metabolism is accounted for by differences in metabolising enzyme activity produced either by enzyme induction, inhibition, or by genetic polymorphism. Liver disease affects bioavailability by changing metabolising enzyme activity and plasma protein binding, and creating intra- and extrahepatic portacaval shunts. In addition, food, by causing transient increases in splanchnic-hepatic blood flow, may also decrease the first-pass metabolism of certain drugs.

The bioavailability of some drugs is dose- and time-dependent. The bioavailability of a single oral dose of 5-fluorouracil, hydralazine, lorcainide, phenacetin (acetophenetidin), propranolol and salicylamide increases as dose increases. When lorcainide, metoprolol, propranolol, dextropropoxyphene (propoxyphene) and verapamil are given repeatedly, their bioavailability increases. This time dependency may not be observed when the drugs are administered intravenously.

The liver has been most extensively studied with respect to first-pass metabolism. Relatively little information is available in humans on intestinal or pulmonary metabolism or on the effects of altered organ blood flow and plasma protein binding on first-pass metabolism. These potentially important areas require further exploration to broaden our understanding of the clinically important phenomenon of first-pass metabolism.

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  1. Clinical Pharmacology Division of the Medical Service, San Francisco General Hospital Medical Center, Bldg. 30, 5th Floor, 1001 Potrero Avenue, San Francisco, CA, 94110, USA

    Susan M. Pond & Thomas N. Tozer

  2. The School of Medicine and the School of Pharmacy, University of California, San Francisco, USA

    Susan M. Pond & Thomas N. Tozer

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Pond, S.M., Tozer, T.N. First-Pass Elimination Basic Concepts and Clinical Consequences. Clin Pharmacokinet 9, 1–25 (1984). https://doi.org/10.2165/00003088-198409010-00001

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