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First-Pass Elimination Basic Concepts and Clinical Consequences

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First-Pass Elimination Basic Concepts and Clinical Consequences Clinical Pharmacokinetics 9: 1-25 (1984) 0312-5963/84/0001-0001/$12.50/0 © ADIS Press Limited All rights reserved. First-Pass Elimination Basic Concepts and Clinical Consequences Susan M_ Pond and Thomas N. Tozer Clinical Pharmacology Division of the Medical Service, San Francisco General Hospital Medical Center, and the School of Medicine and the School of Pharmacy, University of California, San Francisco Summary First-pass elimination takes place when a drug is metabolised between its site ofadmin­ istration and the site ofsampling 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 gas­ trointestinal 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 con­ centration-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 offirst-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 offirst-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 biG­ availability 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 inde­ pendent of concentration and time. The predictions of the models are similar when bio­ availability 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 pre­ cludes 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 me­ tabolite concentration-time profiles after oral and parenteral administration. After an oral First-Pass Elimination 2 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, m/edipine 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 ki­ netics. 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 concen­ tration 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 admin­ istration. 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 of5-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. Rela­ tively 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 me­ tabolism. These potentially important areas require further exploration to broaden our understanding of the clinically important phenomenon offirst-pass metabolism. In clinical practice, drug concentrations are drugs are emphasised and illustrated by clinically measured in peripheral venous blood or plasma. important examples whenever possible. When drug is eliminated between the site of administration and the site of sampling for meas­ 1. Basic Concepts urement, first-pass elimination of the drug has oc­ l.l Organs Involved curred. This elimination is usually assumed to occur via metabolism. First-pass metabolism in the The liver is usually assumed to be the major site gastrointestinal tract and liver of drugs admini­ of first-pass metabolism of a drug administered stered orally has been studied most extensively and orally. Other potential sites after oral administra­ is of importance because most drugs are admini­ tion are the gastrointestinal flora and mucosa, stered orally. First-pass metabolism is important blood, vascular endothelium, lungs, and the limb clinically when the fraction of the dose that escapes in which venous samples are taken. It is difficult loss at these metabolic sites is small and variable. to establish the exact site of drug metabolism after In this review, concepts basic to the process of first­ oral administration by sampling only blood. Po­ pass metabolism are examined. The implications tential sites can be identified in vitro in isolated of first-pass metabolism on the therapeutic use of whole organs, tissue slices, homogenates, or blood First-Pass Elimination 3 enzyme preparations. In animals, identification of arm and sampled in the other, the product is involvement of the intestine and liver can be achieved by comparing the areas under the plasma Fiv = FLu • FA • FB (Eq. 2). concentration-time curve (AVC) after intravenous, Combining equations 1 and 2 results in oral and intraportal drug administration (Iwamoto and Klaassen, 1977a,b; Rheingold et aI., 1982; Rowland, 1972). Similar manipulations of route of (Eq. 3). administration can identify other potential sites of metabolism, such as the lungs (Brazzell et aI., 1982). By definition, Fiv is conventionally assigned a value In humans, the portal vein has been catheter­ of unity. Thus, the bioavailability of an orally ad­ ised to study the first-pass metabolism in the in­ ministered drug is then the product of the fractions testine of oral doses of flurazepam (Mahon et aI., entering the irttestinal wall and escaping loss in the 1977) and proscillaridin (Andersson et aI., 1977). intestine and liver. It should be clear from equa­ The kinetic behaviour of intraperitoneal, intraven­ tion 2 that the assignment of unity to Fiv is arbi­ ous (Collins et aI., 1980), or intrahepatic arterial trary. Consequently, the application of the term doses (Ensminger et aI., 1978) of 5-fluorouracil has 'absolute bioavailability' to the value obtained from also been examined. Shand and Rangno (1972), by comparison with intravenous administration may studying a patient who had a surgical portacaval be inappropriate when elimination occurs in the anastamosis, showed that the intestine does not lungs, arm, blood or vascular endothelium. metaboIise propranolol. In other studies, the first­ pass uptake and elimination of compounds by the 1.3 Pharmacokinetic Considerations lungs have been studied in patients undergoing routine cardiac catheterisation (Geddes et aI., 1979; When the liver is the sole site of loss, Jose et aI., 1976). Woodcock and co-workers
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