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 (1981) Foral = 1 - E (Eq.4), directly measured the hepatic extraction of vera­ pamil in cardiac patients. where E is the extraction ratio, i.e. the fraction of drug entering the liver that is eliminated by the 1.2 Concept of Bioavailability organ. Vnder steady-state conditions, the rate of extraction of drug by the liver [the product of the BioavaiiabiJity - defined as the ratio of the AVCs hepatic (H) blood clearance (CLHB) and the con­ (corrected for dose if necessary) after extra- and centration of drug in blood (C )] equals the rate of intravascular drug administration (Tozer, 1979) - B presentation of the drug to the liver [the product is often used as a measure of the extent of first­ of liver blood flow (em) and C ]. Consequently, pass metabolism. When several sites of first-pass B the extraction r!itio is, by definition: metabolism are in series, the availability of the drug can be viewed as the product of the fractions of CLHB' CB drug entering the tissue that escape loss in each E = QH' CB successive tissue. Thus, the product (Foral) for an orally administered drug that is metabolised in the (Eq. 5). gastrointestinal lumen (G), the intestinal wall (I), liver (L), lung (Lu), arm (A), and blood and endo­ Therefore, thelial linings or the vascular system (B) is Foral = 1 - (CLHB/QH) (Eq. 6). (Eq. 1) Equation 6 indicates that the relative changes in When intravenously (iv) administered in one the two pharmacokinetic parameters CLHB and F oral First-Pass Elimination 4

will not be the same. For example, if clearance de­ data when 4 parameters are known: the ratio of creases from 99 to 97% of blood flow, a 2% de­ blood-to-plasma concentrations; plasma clearance crease, the bioavailability increases from 0.01 to (CLp); fraction of drug in the body that is excreted 0.03, a 200% increase. unchanged in urine (fe); and liver blood flow. Blood Equations 5 and 6 use hepatic clearance calcu­ clearance (CLB) is calculated first using equation 9. lated from drug concentrations in whole blood, CB. The fraction undergoing non-renal elimination However, most clinical pharmacokinetic informa­ is (1 - fe)' If the liver is assumed to be the sole tion has been obtained from plasma drug concen­ non-renal organ of elimination, the hepatic blood trations. Plasma flow and plasma drug concentra­ clearance (CLBB) is then tion of drug (Cp) cannot be substituted into (Eq. 10). equation 5 unless the drug is confined to plasma (Rowland, 1972), in which case Cp = C • [1 - B By substituting equations 9 and 10 into equation Haematocrit (Hct»). In all other cases the blood-to­ 6, bioavailability becomes plasma concentration ratio must be determined. The relationship between blood and plasma drug (l-fe)· CLp concentrations depends on the haematocrit and the Foral = I - (Eq. 11). relative affinities of the drug for blood cells and QB • CB/Cp plasma proteins. This conclusion can be derived The importance of knowing the blood-to-plasma from the principles of mass balance, in that drug concentration ratio is illustrated by the. fol­ lowing example. Consider 2 drugs with plasma V BC • CBC clearance values of 1500 ml/min, negligible excre­ + I i (Eq. 7), == tion in urine, and blood-to-plasma concentration Amount Amount Amount in in blood in plasma blood cells ratios of 1.1/1 and 100/1. Assuming an hepatic blood flow of 1500 ml/min, the oral bioavailabil­ where VB, V p, and V Be are the volumes of blood, ities of the 2 compounds calculated from equation plasma, and red blood cells, respectively, and CB, 11 are 0.09 and 0.99, respectively. These values are Cp, and eBC are the concentrations of drug in these greatly ditTerent even though the plasma clearances respective volumes; V Be/V B is the haematocrit and are identical. Vp/VB = I - Hct. Dividing by (VB· Cp) gives 1.4 Non-Linear First-Pass Metabolism CB . CBC - = (I-Hct) + Hct· - (Eq. 8). Cp Cp The bioavailability of somt! compounds changes with dose. For example, bioavailabilities of ribo­ The ratio ofbloodlplasma drug concentrations, CBI flavine (vitamin B ) [Levy and Jusko, 1966] and Cp, lies between the limits of(l - Hct) and a larger 2 cyanocobalamin (vitamin Bd (Diem, 1962) de­ value determined by the relative affinities of drug crease with increasing doses because of capacity­ for blood cells and for plasma proteins. limited transport. Conversely, the bioavailability Clearances based on drug in whole blood (CLB) of propranolol increases as dose increases (Shand and in plasma (CLp) are related by and Rangno, 1972) because of limited capacity of (Eq. 9). the metabolising hepatic enzymes (Walle et aI., 1981). Theoretically, saturable binding of drug to This relationship is obtained from the definition plasma proteins could also produce non-linear first­ of clearance values, that is, rate of elimination = pass metabolism. CLp • Cp = CLB • CB' First-pass metabolism after oral doses may be Whether or not a drug undergoes extensive first­ non-linear when metabolism after intravenous pass elimination can be anticipated from plasma doses, administered on separate occasions, is not. First-Pass Elimination 5

The reason lies in the difference between the con­ tration ratio is large only if absorption is fast. Thus, centration of drug entering the liver after each route the potential for non-linear first-pass metabolism of administration. Consider the oral administra­ exists when absorption is fast and/or the apparent tion of a drug eliminated only in the liver and with volume of distribution is large. I-compartment characteristics. Assuming that the Figure 1 was simulated when the oral and intra­ absorption into the portal vein is first-order, the venous doses were given on separate occasions. It initial rate of input of drug is ka • dose, where ka is important to note that if an intravenous radio­ is the absorption rate constant. The initial rate of labelled tracer dose is given concurrently with an entry of drug into the liver is Q,v • Cpv, where oral dose, the intravenous kinetics will reflect the Q,v is the portal blood flow and Cpv is the drug non-linear first-pass metabolism during absorp­ concentration in the portal vein blood as it enters tion, but may be non-linear over too short a time the liver. Anatomically, the hepatic artery adds to to be measurable. portal blood flow. So, the rate of entry of drug may be expressed as ~ • CA where ~ is the total liver Influence of Dosage Form blood flow and CA is the concentration of drug The dosage form of a drug can have an impact measured after dilution by hepatic arterial blood. on non-linear first-pass metabolism. From the ar­ The initial rate of presentation of drug to the liver gument above, the concentration entering the liver after a single oral dose is depends on the rate of entry of drug into the portal vein. The slower the rate of release from a dosage (Eq. 12). form, the lower the concentration entering the liver. Thus, slow absorption from a sustained release On rearrangement, the initial concentration enter­ ing the liver is

(Eq. 13).

\ Vd(L) After a single intravenous dose (iv), the corre­ sponding concentration is ~ (Eq. 14), where Vd is the apparent volume of distribution of the drug. If the oral and intravenous doses are the same, the ratio of these resulting concentra­ tions is

CA.oral (Eq. 15). Absorption half-life (minutes) CA.iv

Figure 1, derived from equation 15, illustrates Fig. 1. The ratio of the initial drug concentrations entering the how this ratio varies with the absorption half-life liver after an oral dose and after the same intravenous dose (O.693/ka) and the apparent volume of distribution varies with the absorption half· life and the apparent volume of (V d). If Vd is large (> 200L) the initial concentra­ distribution (Vd). The shorter the absorption half-life and the larger the apparent volume of distribution, the greater the ratiO. This tion entering the liver after an oral dose is much figure was obtained by simulation of equation 15; the absorption greater than that after an equivalent intravenous half-life = O.693/ka . The following assumptions were made: dis­ dose at all of the absorption half-lives shown. On tribution is instantaneous, absorption and elimination are first­ the other hand, if Vd is small « SOL) the concen- order processes, and the liver is the sole site of elimination. First-Pass Elimination 6

dosage form may not show non-linear bioavaila­ models used to predict the dependence of F on flow bility, whereas rapid absorption of the same dose are discussed in section 1.6. given in solution or a rapidly dissolving dosage form may show non-linear bioavailability. This Plasma Protein Binding probably explains the much greater apparent bio­ Increasing plasma protein binding increases availability of salicylamide given as a suspension bioavailability; the converse is also true. However, than as a solid dosage form (fleckenstein et ai., the extent of the changes is difficult to predict 1976). quantitatively. Two models used to predict the de­ pendence of bioavailability on protein binding are 1.5 Physiological Variables Involved in discussed in section 1.6; these models differ mark­ First-Pass Metabolism edly in their estimates of the degree of change. The theoretical predictions are difficult to verify in hu­ The extent of first-pass metabolism in the liver mans because factors that alter plasma protein and intestinal wall depends on a number of phys­ binding usually also alter other physiological vari­ iological factors. The major ones are enzyme ac­ ables such as blood flow and hepatic enzyme ac­ tivity, plasma protein and blood cell binding, blood tivity. For example, phenobarbitone increases the flow, and gastrointestinal motility. plasma protein binding of propranolol in the dog but also enhances hepatic metabolising enzyme ac­ 1.5.1 Hepatic First-Pass Metabolism tivity and probably increases liver blood flow (Bai and Abramson, 1982; Vu et ai., 1983). Enzyme Activity The inherent enzyme activity is usually the most Gastrointestinal Motility important determinant of the extent of first-pass Gastric emptying and intestinal motility affect metabolism. The activity is commonly expressed the rate of absorption of drugs and may also influ­ in terms of the Michaelis-Menten parameters, Vm ence the extent of first-pass metabolism in the liver (the maximum rate of metabolism) and Km (the if the metabolism is non-linear. Increasing gas­ concentration at which the rate of metabolism is trointestinal motility may increase the rate of de­ Vm/2). The value of Vm is related to amount of livery of drug to the liver. If metabolism is non­ enzyme present and the capacity per mole of en­ linear, this increased delivery will result in in­ zyme. In classic enzyme kinetics creased bioavailability. The converse is anticipated Vm· S when gastric emptying is delayed or intestinal mo­ Rate of metabolism = (Eq. 16), tility is diminished. Km+S where S is the substrate concentration. Saturability 1.5.2 First-Pass Metabolism in the or non-linearity occurs when S approaches and ex­ Gastrointestinal Mucosa ceeds the value of Km; the rate then approaches When the primary site of first-pass metabolism Vm. The relationship in equation 16 often ade­ is the intestinal mucosa, the expected direction of quately explains the kinetics of drug metabolism the effects of altered enzyme activity, blood flow, in vitro, but there are many additional factors in and plasma protein binding on bioavailability are vivo that must be considered, including blood flow similar to those for the liver. However, the reasons and the supply of co-factors. for the relationships are different. In the intestinal mucosa, drug diffuses to the enzymes, and drug Blood flow and metabolites are removed by the blood. One Increasing blood flow increases bioavailability; might speculate that blood acts as a sink. As a con­ the converse is also true. The extent of the change sequence, when blood flow is increased, drug may depends on the extraction ratio of the drug. Two be removed from the mucosa to a greater extent, First-Pass Elimination 7

'Well-stirred' model 'Parallel tube' model 0.20 0.20

0.16 0.16 0.06~" ~ 0.12 0.12 is ~ 0.08 0.08 > iij'" 0.04 0.04

0.00 0.00 a Intrinsic clearance (L/min) b Intrinsic clearance (L/min)

0.20 0.20

0.16 0.16

~ 0.12 0.12 is .!!! 'iii 0.08 > '"0 CD 0.04

0.00 C Blood flow (L/min) d Blood flow (L/min)

0.20 0.20

0,16

~0,12 0.12 is ~'" 0.08 > '"o iii 0.04 0.04

o.oo-~=-""'~~~""'"":~~ e Fraction unbound f Fraction unbound

Fig.2. The 'well-stirred' and 'parallel tube' models (see text) of hepatic extraction of drugs differ in their prediction of the effects on bioavailability of changes in intrinsic clearance (figs a and b) at different fractions unbound (fu); blood flow (figs c and d) at different fractions unbound; and fraction unbound in blood (figs e and f) at different blood flows (0). Whet! not specified, intrinsic clearance and blood flow were given the values of 60 and 1.5 Llmin, respectively. First-Pass Elimination 8

resulting in increased bioavailability. Decreased flow, and plasma protein binding. Note that the plasma protein binding may reduce the ability of 'parallel tube' model always predicts a much greater blood to pick up the drug, thus reducing bioavail­ change in F than the 'well-stirred' model for a given ability. The potential effects of altering gastroin­ change in intrinsic clearance, blood flow, or frac­ testinal motility are unpredictable. tion unbound. Because these two models summarise quanti­ 1.6 Models of First-Pass Metabolism tatively the expected relationships between bio­ in the Liver availability and changes in enzyme activity, blood flow and protein binding, they may be useful. Models that describe dependence of bioavaila­ However, they must be tested for thdr validity, and bility on changes in enzyme activity, blood flow, drugs with low bioavailability due to extensive first­ and plasma protein and blood cell binding have pass hepatic metabolism provide tools for doing been developed. Two that have been applied widely so. Similarities and differences between the two are the 'well-stirred' model (Rowland et aI., 1973; models have been examined (Ahmad et aI., 1983; Wilkinson and Shand, 1975) and the 'parallel tube' Pang and Rowland, I 977a,b,c). The 'well-stirred' model (Brauer, 1963; Winkler et aI., 1973, 1974). model describes the hepatic elimination of pro­ In a 'well-stirred' model, the liver is treated pranolol (Branch and Shand, 1976) and lignocaine as a well-stirred container in which the unbound (Pang and Rowland, 1977b,c). The 'parallel tube' drug concentration in hepatic venous blood is the model describes the elimination of galactose in the concentration available to the metabolising en­ perfused pig liver (Keiding et aI., 1976; Keiding and zyme(s). In this model, the fraction of incoming Chiarantini, 1978). drug that escapes metabolism in the liver (F d is Without modification, these models are ex­ pected to be inadequate to predict bioavailability QH (Eq. 17), in vivo when metabolism is non-linear, hepatic QH + CLint' fUB blood flow is shunted, drug undergoes enterohe­ patic recycling, or metabolism occurs in other first­ where ~ is hepatic blood flow, CLint is the in­ pass organs. trinsic clearance, which relates the rate of metab­ olism to the unbound drug concentration in he­ 2. Clinical Consequences of First-Pass patic venous blood, and fUB is the unbound fraction Elimination of drug in blood. 2.1 Route of Administration and In the 'parallel tube' model, the liver is treated Bioavailability as a series of equivalent parallel tubes that have constant enzyme activity along the length of each 2.1.1 Oral Administration tube. Drug concentration in perfusing blood de­ Many clinically important drugs undergo con­ creases along the tube. The fraction escaping loss siderable first-pass metabolism after an oral dose. in this model is The characteristics of selected drugs that undergo (Eq. 18), 50% or more first-pass metabolism after an oral dose are presented in table I. Although many of where fU B and Q; are as defined above, and CLint the drugs listed in the table undergo first-pass me­ relates the rate of metabolism to the average un­ tabolism in the liver, some are metabolised by in­ bound concentration within the tube. testinal flora or mucosa. Drugs metabolised in the These models are similar in their predictions intestine include levodopa, flurazepam, isoprena­ when bioavailability is large but differ dramatically line, ~-methyldigoxin, oestrogen, phenacetin and when bioavailability is small. Figure 2 shows how salicylamide (George, 1981), and proscillaridin bioavailability changes with enzyme activity, blood (Andersson et ai., 1977). First-Pass Elimination 9

The major therapeutic implication of extensive site of administration and the site of blood sam­ first-pass metabolism is that much larger oral than pling. When 2% glyceryl trinitrate ointment was intravenous doses are required to achieve equiv­ applied to the skin of the left wrist, contralateral alent plasma concentrations. For some of these antecubital venous blood concentrations of gly­ drugs, the extent of first-pass metabolism, at least ceryl trinitrate did not exceed 0.1 ng/ml (AzarnotT in part, precludes their use as oral agents. Com­ et aI., 1983). In contrast, blood from ipsilateral veins pounds in this category include lignocaine, nalox­ had mean peak concentrations of 12 ng/ml. These one, glyceryl trinitrate (nitroglycerin), and dihy­ site-related ditTerences in apparent bioavailability droergotamine. Despite its low bioavailability, are reflected by significant differences in the re­ dihydroergotamine can be used orally to treat some sponse of normal subjects to glyceryl trinitrate when patients with orthostatic hypotension, probably be­ the same doses are applied to ditTerent body sites cause they have greater sensitivity to the drug's (Hansen et aI., 1979). vasoconstricting effects (Bobik et aI., 1981). The lack of pharmacological activity and bio­ 2.1.3 Inhalation and Buccal Administration availability of oral naloxone (Fishman et aI., 1973) Societies have known for hundreds of years that has been utilised recently in a novel formulation inhalation of nicotine or opium produces the de­ of pentazocine tablets (Talwin® Nx, package insert, sired effect, whereas oral administration either does Winthrop Laboratories, New York) to prevent their not or requires much larger doses. Drugs given by injection intravenously by drug abusers (Poklis and inhalation include sympathomimetic agents and Mackell, 1982). The combination of pentazocine corticosteroids used to treat asthma. These are given and naloxone taken orally has the desired analgesic by inhalation to deliver the drug directly to their effect. In contrast, no effect is experienced when sites of action. Some do undergo extensive first­ the tablets are crushed and injected intravenously pass metabolism after oral administration, e.g. sal­ because the naloxone, now fully bioavailable, blocks butamol (Evans et aI., 1973) and isoprenaline the pentazocine effect. (Blackwell et aI., 1973). Because the lung plays only a small role in the biotransformation of these com­ 2.1.2 Transdermal Delivery pounds, inhalation of these drugs might be ex­ Clinicians apply drugs topically to treat various pected to give the metabolite pattern expected of skin diseases but have only recently begun to use an intravenous dose. However, after administra­ the skin to reach the general circulation. Topical tion of 3H-salbutamol by inhalation of an aerosol dosage forms of glyceryl trinitrate provide an ex­ form, 55% of the radioactivity in urine over the ample of this latter use. Glyceryl trinitrate has a first 24 hours was recovered as metabolite, similar short elimination half-life (1.3 to 3.8 minutes), a to the 61 % after oral administration; in contrast large apparent volume of distribution (1.7 to 5.2 only 27% was recovered as metabolite after intra­ L/kg), and a high plasma clearance (0.3 to 1.0 L/ venous administration (Evans et aI., 1973). Inhaled min/kg) [McNitT et aI., 1981]. Transdermal deliv­ isoprenaline also behaves pharmacokinetically like ery of glyceryl trinitrate has been developed, in part, an oral dose, with the majority of the drug under­ to avoid hepatic first-pass metabolism of an oral going sulphation - not O-demethylation, the fate of dose. However, the transdermally delivered drug an intravenous dose (Blackwell et aI., 1973). These still undergoes some first-pass metabolism in the data indicate that most of the drug inhaled as an skin (Wester et aI., 1981), blood, and vascular aerosol is eventually swallowed. Presumably, most endothelium (Armstrong et aI., 1980; Fung and of the aerosol is trapped in the upper airway be­ Kamiya, 1981; Wu et aI., 1981). The volume of cause of the large droplet size. blood and surface area of the vascular endothelium Sublingual or buccal administration of a drug to which the drug is exposed are among the factors may produce blood concentrations similar to those that dictate the extent of metabolism between the of an equivalent intravenous dose. This similarity Table. I. BioavailabiJity (F) of some drugs that undergo extensive first-pass metabolism (> 50%) in man after oral administration. Values of F are ranges or mean ± SO ';!I. reported in the literature, usually after single oral doses calculated with reference to an intravenous dose ~ ;;l' Drugs Bioavailability (F) Active metabolites Comments Reference(s) I:l t!l baseline increased by decreased by S' conditions (usually in o~: normal subjects) I:'

~-Adrenoceptorblocking drugs Alprenolol 0.01-0.28 Increasing single Pentobarbitone 4-Hydroxyalprenolol Metabolite and drug Ablad et al. (1974); Alvim et al. dose equipotent (1977a,b,c); Collste et al. (1979a,b)

Labetolol 0.33 ± 0.08 Cirrhosis; food Pentobarbitone Has a-blocking Homeida et al. (1978); Mantyla et al. properties (1980)

Metoprolol 0.21'0.86 Repeated dosing; a-Hydroxymetoprolol Oxidation phenotype of Haglund et al. (1979); Jordo et al. cirrhosis; food debrisoquine type (1980); Lennard et al. (1982); determines metoprolol Melander et al. (1977); Regardh and hydroxylation Johnsson (1980)

Oxprenolol 0.19-0.74 Inflammatory Kendall et al. (1979); Mason and diseases Winer (1976)

Propranolol 0-0.28 Increasing single 4-Hydroxypropranolol MetabOlite and drug Cleaveland and Shand (1972); Evans dose; equipotent; saturation of and Shand (1973); Kornhauser et al. chlorpromazine; food; napthalene ring oxidation (1978); McLean et al. (1980); hydralazine; cirrhosis; is main determinant of Melander et al. (1977); Schneck and inflammatory disease bioavailability; first-pass Vary (1983); Schneider and Bishop metabolism is (1982); Shand and Rango (1972); stereoselective Shand et al. (1970); Silber et al. (1982); Vestal et al. (1979); Walle et al. (1980, 1981); Wood et al. (1978)

Analgesic drugs Codeine 0.42-0.71 Morphine Findlay et al. (1977)

Dextro- 0.29-0.70 Cirrhosis; repeated Norpropoxyphene MetabOlite toxic; higher Giacomini et al. (1980); Gibson et al.

propoxyphene doses AUCoral in renal failure (1980); Gram et al. (1979); Inturrisi et al. (1982)

Morphine 0.15-0.64 F determined in patients Brunk and Delle (1974); Sawe et al. with cancer (1981) Pentazocine 0.11-0.32 Cirrhosis Ehrnebo et al. (1977); Neal et al. (1979); Pond et al. (1980) -o :!1 Pethidine 0.47-0.73 Cirrhosis Phenytoin Norpethidine Norpethidine may Edwards et al. (1982); Mather and .... ~ (meperidine) produce neuromuscular Tucker (1976); Neal et al. (1979); .;, excitability Pond et al. (1980,1981); Szeto et al. I» '" (1977); Verbeeck et al. (1981) t!l a· Phenacetin 0-0.08 Increasing single Cigarette smoking Paracetamol Intestinal metabolism Pantuck et al. (1972); Raaflaub and s· (acetophenetidin) dose (acetaminophen) Dubach (1975) I» g. Opiate antagonists ::l

Naloxone 6-~-Hydroxynaloxone Drayer (1976); Fishman et al. (1973)

Antiarrhythmic drugs Encainide 0.07-0.82 Inherited deficiency O-Demethylencainide Inherited deficiency of Gomoll et al. (1981); Roden et al. of hydroxylation 3-Methoxy-O- hydroxylation of (1982); Wang et al. (1982); Winkle et demethylencainide debrisoquine type leads al. (1981); Woosley et al. (1981) to F of almost 1 and no antiarrhythmic activity

Lignocaine 0.21-0.46 Cirrhosis Cigarette Monoethyl­ Metabolites toxic Bennett et al. (1982); Boyes et al. (lidocaine) smoking, glycinexylidide (1971); Drayer (1976); Huet and anticonvulsant Glycinexylidide LeLorier (1980); Huet et al. (1978); drugs Perucca and Richens (1979); Tschanz et al. (1977)

Lorcainide 0-0.89 Increasing single Norlorcainide Jiihnchen et al. (1979); Kates et al. dose; repeated doses (1983); Meinertz et al. (1979)

Quinidine 0.44-1.06 3(S)-Hydroxyquinidine Bioavailability may be Guentert et al. (1979); Holford et al. O-Demethylquinidine increased with repeated (1981); Ochs et al. (1978); Ueda et 2'-Oxoquinidine doses and at higher al. (1976); Yu et al. (1982) doses due to non-linear metabolism

Calcium antagonists Nifedipine 0.45 ± 0.08 McAllister et al. (1982)

Verapamil 0.12-0.33 Norverapamil Increased bioavailability Eichelbaum et al. (1980, 1981); on repeated dOSing is Freedman et al. (1981); Kates et al. controversial (1981); McAllister and Kirsten (1982); Reiter et al. (1982); Shand et al. (1981); Wagner et al. (1982) vasoactive drugs Dihydro- 0.001-0.015 Oral glyceryl trinitrate Bobik et al. (1981) ergotamine

First-Pass Elimination 13

has led to the sublingual application of glyceryl tri­ olism are found after oral doses than after intra­ nitrate, methyltestosterone (Alkalay et aI., 1973), venous doses, even if plasma concentrations of the ergotamine (Ala-Hurula et al., 1979), and intra­ parent drug achieved after each route are similar. tracheal use of naloxone and adrenaline (epineph­ Sometimes, metabolites have been detected in rine) during cardiopulmonary resuscitation. plasma only after an oral dose. Drugs in one or

2.1.4 Rectal Versus Oral Administration Because the rectum has a small surface area, drug absorption via this route is usually slow and can be incomplete. Drugs are administered rectally 100 .. when local therapy is desired, the oral route can not be used, or to bypass first-pass metabolism. However, the last rationale has had only partial 50 success. Only the lower third of the rectum is drained by veins that do not enter the hepatic por­ tal circulation. de Boer and co-workers (1979) stud­ ied the bioavailabiIity of lignocaine in healthy sub­ 20 jects who were given 200mg intravenously, 300mg oraJly or 300mg rectally. The mean bioavailability 0· ... after rectal administration (63%) was higher than , \ that after oral administration (31 %). J onkman et 10 ,, , , •\ al. (1979) studied the quaternary ammonium com­ \ \ pound thiazinamium methylsulphate, which is used 2: o, \ (5 \ to treat chronic obstructive pulmonary lung dis­ 5 I \ E , \ ease, given rectally, orally and intramuscularly. The .s , \ c: , \ mean bioavailability after rectal administration (6.2 o . ± 3.4%) was similar to that after an oral dose ~ o • C Q) (3.6 ± 1.7%). () c: 2 The clinical utility of the rectal route of admin­ 8 istration has been reviewed recently (de Boer et al., E'"

Drugs that undergo extensive first-pass metab­ olism may produce different plasma metabolite o 50 100 concentration-time profiles after oral and paren­ Time (hours) teral administration. As shown in figure 3, the con­ centration of the metabolite, nortriptyline, reaches Fig. 3. Plasma concentration-time curves for amitriptyline (solid a peak earlier after an oral dose of amitriptyline symbols) and its major metabolite, nortriptyline (open symbols), than after an intramuscular dose (Mellstr6m et al., after administration of a single 50mg oral dose (-) and a 25mg 1982). This arises because entry of metabolite into intramuscular dose (---) of amitriptyline to a normal subject. the general circulation after an oral dose is more The plasma concentrations of nortriptyline reached a peak earl­ ier after the oral than after the intramuscular dose of amitrip­ rapid than after a parenteral dose. Furthermore, tyline. [From Mellstrom et aI., Clinical Pharmacology and Thera­ higher plasma concentrations of the metabolites of peutics 32: 664 (1982); reproduced with permission of the authors many drugs subject to extensive first-pass metab- and publisher.j First-Pass Elimination 14

both of these categories include alprenolol (Collste phine (Brunk and Delle, 1974). A similar phen­ et aI., I 979a,b), amitriptyline (Schulz et aI., 1983), omenon has also been demonstrated in humans for 10rcainide (Jiihnchen et aI., 1979), pethidine (Pond amitriptyline/nortriptyline (Mellstr6m et aI., 1982) et aI., 1981), nifedipine (McAllister et aI., 1982), and for acetylsalicylic acid/salicylic acid (Rowland dextropropoxyphene (Gram et aI., 1979), propran­ et aI., 1967). However, if any of these conditions olol (Walle et ai., 1981), and verapamil (McAllister are not met, the fraction of the dose administered and Kirsten, 1982). that is converted to a metabolite may vary with Although the concentration-time profiles of me­ the route of administration. Drugs in this category tabolites may differ after oral and parenteral doses, include isoprenaline and salbutamol (see also sec­ the fraction of a dose converted eventually to a tion 2.1.3). metabolite should be the same after each route of Variation in the concentration ratios between administration - provided that the ingested drug parent drug and metabolite may produce route-de­ is completely absorbed, is solely eliminated by me­ pendent differences in the pharmacological or tabolism in the liver, and exhibits linear kinetics. toxicological response to a given concentration of Under these conditions, the dose is equally avail­ the parent drug, e.g. with encainide, lorcainide, able to the metabolising organ after either route of quinidine and verapamil. Winkle and co-workers administration, as illustrated in figure 4 for mor- (1981) found that minimal antiarrhythmic plasma

70 ...... ::.: !::::.:.::::::::::::::::::::::::::.::::.:::::::::::::::::: :::::::::::::::::::;::: t .. l····.... ~!- I~I~ 50 .• 2~~ Ii····r 30 Ii .-.Intravenous i1 0··.····0 Intramuscular ..~ IJ A-A SUbcutaneous If •...... • Oral /R 10 II i 2 4 6 9 12 18 24 30 36 42 48 Time (hourS)

Fig. 4. The route of administration has no effect on the excretion of conjugated morphine in the urine. Values are expressed as the cumulative percentage (mean ± SE) of the administered dose that was excreted as metabolite in the urine. The 48-hour excretion of conjugated morphine was similar after the administration of 5.75mg of ('4C-N-methyl) morphine sulphate/m2 of body surface area to 6 subjects at weekly intervals by 4 routes: intraVenous. intramuscular. subcutaneous and oral. [From Brunk and Deile, Clinical Pharmacology and Therapeutics 16: 51 (1974); reproduced with permission of the authors and publisher.] First-Pass Elimination 15

concentrations of encainide were higher in 6 of 8 Concentrations of lorcainide required to produce patients after intravenous than after oral admin­ the same widening of the QRS interval were lower istration. An active metabolite, O-demethylencain­ after oral than after intravenous administration. ide, on which most of the drug's antiarrhythmic These differences were attributed to the large input activity probably depends, is produced rapidly after of an active metabolite formed during first-pass oral administration (Roden et at., 1982; Wang et metabolism (fig. 5). a\., 1982). In contrast, Eichelbaum and co-workers (1980) In another study, Meinertz and co-workers demonstrated that at the same plasma concentra­ (1979) demonstrated that plasma concentration tion of vera pam iI, prolongation of the P-R interval versus effect curves of lorcainide were different after was greater after intravenous than after oral intravenous and oral administration of the drug. administration of the drug. They suggested that the most plausible explanation for the route-dependent differences in response was that first-pass metab­ olism selectively eliminated the active stereoiso­ 50 mer of verapamil, although this has been ques­ 441.5 tioned by Reiter et at. (1982). 2.0 Holford et at. (198\) examined the contribution of quinidine metabolites to cardiac repolarisation 40 by comparing the change in Q-T interval of the

43.0 electrocardiogram at a given quinidine concentra­ tion after oral and intravenous doses. The greater e 30 44.0 response after oral than after intravenous admin­ C istration was attributed to the rapid formation of 0 " 0.05 active quinidine metabolites during first-pass '0 ~6f50 t 2.0.6 80 0.12 metabolism. Ol 20 c: 'c 3.0 11 CD e eO.17 2.3 Variability in First-Pass Metabolism '0 0.25 .~ AD,5 en 4.0{.61.0 0.5 cr 5. 2.3. I Clinical Importance a 10 3.00 6.0 2.0 8.0 It is well-established that the response to drugs varies widely among individuals. Drugs that undergo extensive first-pass metabolism exhibit pronounced interindividual variation in plasma 0.02 0.04 0.1 0.4 1.0 concentrations or drug concentration-time curve Plasma lorcainide concentration (ltg/ml) after oral administration. This variability, often re­ flected by drug response, poses one of the major problems in the clinical use of these drugs. Fig. 5. Plasma concentration-electrocardiographic effect (ORS widening) response curves of lorcainide after single oral doses Although a lot of the interindividual differences (0 = 150mg; 6 = 300mg; 4 = 500mg) and after an intravenous in bioavailability of drugs subject to extensive first­ dose of 136mg (e) in 1 subject. A linear relationship between pass elimination can be accounted for by differ­ both variables was found. but the plasma concentration-effect ences in metabolism, some may not. Walle and co­ curves after oral administration differed from those after intra­ workers (1978) showed in a meticulous study with venous administration. lower plasma concentrations of lorcain­ ide were required after oral than after intravenous doses to pro­ oral administration that the interpatient variation duce the same pharmacodynamic effect [From Meinertz et al.. in steady-state propranolol plasma concentrations Clinical Pharmacology and Therapeutics 26: 196 (1979); repro­ was 3-fold. This contrasted with the previously re­ duced with permission of the authors and publisher.j ported 10- to 20-fold variations found in other First-Pass Elimination 16

studies cited by Walle et al. (1978). Their study (15.44 ± 2.34 ml/min/kg) were similar (Huet and demonstrated that not only do differences in me­ LeLorier, 1980), whereas bioavailabilities were sig­ tabolism contribute to the apparent variations, but nificantly different, 0.45 ± 0.09 versus 0.16 ± 0.14, also patient compliance, achievement of steady­ respectively. Metyrapone inhibits ll-~-hydroxyl­ state conditions, sampling technique, time of col­ ase activity in the adrenal gland, leading to hypo­ lection and assay methods. thalamic release of adrenocorticotrophin. Patients It is also important to remember that bioavail­ treated long term with phenytoin have much lower ability reflects all of the physiological factors dis­ plasma concentrations of unconjugated metyra­ cussed in section 1.5. Clinical situations in which pone after a single 7S0mg oral dose of the drug more than 1 factor is altered can lead to unpre­ than normal subjects (Meikle et al., 1969). The dictable changes in bioavailability, which must clearance of metyrapone was not altered by pheny­ therefore be measured; for example, in patients with toin but the differences in plasma concentrations thyrotoxicosis, plasma protein binding, intrinsic after oral administration of metyrapone in the 2 clearance of propranolol and hepatic blood flow are groups were reflected by a lack of response to the greater than in patients who are euthyroid (Wells oral form of the drug in the phenytoin-treated et aL, 1983). The overall effect of these changes is patients. Both groups of patients, however, had that bioavailability, measured at steady-state, is not similar responses when metyrapone was given significantly different when patients are thyrotoxic intravenously (Meikle et al., 1969). or euthyroid. The situations discussed below, in 2. Genetic polymorphism: This may also be re­ which only I of the individual physiological factors sponsible for interindividua1 variations in first-pass is altered, are probably the exception rather than metabolism. Examples are provided by encainide, the rule. hydralazine, and metopro1ol. The bioavailability of encainide in 8 'normal' subjects was 0.26 ± 0.19 2.3.2 Factors that Account for Variability (Roden et aL, 1983); in contrast, the bioavailability in First-Pass Metabolism in 2 subjects who were presumably genetically de­ ficient in the enzyme required to O-demethylate Differences in Metabolising Enzyme Activity encainide was close to LO. For hydralazine, the I. Enzyme induction or inhibition: Both the bioavailabilities in 2 fast acetylators were 0.26 and physiological models discussed in section 1.6 pre­ 0.36, and in 2 slow acetylators 0.45 and 0.55 (Tal­ dict that altering intrinsic clearance affects bio­ seth, 1976b). As shown in figure 6, the area under availability more than clearance. Examples are the metoprolol plasma concentration-time curve provided by studies of alprenolol, propranolol, after an oral dose of 200mg was 7250 ± 1220 lignocaine, and metyrapone. Administration of ng/ml • h in poor hydroxylators and 1246 ± 796 pentobarbitone sodium for 10 to 14 days to 5 ng/ml • h in extensive hydroxylators of the drug healthy subjects did not alter the clearance of al­ (Lennard et al., 1982). The traits for impaired me­ prenolol (Alvan, 1977b,c); in contrast, the mean tabolism of debrisoquine, metoprolol and encain­ bioavailability of a 200mg oral dose decreased from ide appear to be co-inherited (Roden et al., 1983). 0.28 ± 0.13 to 0.07 ± 0.01. Chlorpromazine in­ hibits the metabolism of propranolol (Vestal et al., Liver Disease 1979). In 5 subjects given chlorpromazine, the bio­ The bioavailability of some drugs subject to ex­ availability of propranolol increased from 0.25 ± tensive first-pass metabolism in the liver may be 0.07 to 0.32 ± 0.09; in contrast, clearance de­ increased in some forms of liver disease (Blaschke creased only in 3 subjects and the change was less and Rubin, 1979). Cirrhosis is the usual form of pronounced than that in bioavailability. liver disease studied. The bioavailabilities of chlor­ The plasma clearances of lignocaine in 5 non­ methiazole, labetalol, lignocaine, metoprolol, pen­ smokers (13.45 ± 3.00 ml/min/kg) and 4 smokers tazocine, pethidine, dextropropoxyphene and pro- First-Pass Elimination 17

pranolol are increased in patients with cirrhosis of Figure 7 illustrates the expected effects, accord­ the liver (Blaschke and Rubin, 1979); for example, ing to the 'well-stirred' and 'parallel tube' models in cirrhotic subjects, the bioavailabilities of peth­ (section \.6), of shunting of hepatic blood flow on idine, pentazocine and propranolol were 42%, 81 %, bioavailability when intrinsic clearance, blood flow and 278% greater, respectively, than normal values or fraction of unbound drug is changing. Bioavail­ (Neal et aI., 1979; Wood et aI., 1978). ability can only decrease to a value limited by the The major physiological factors that increase the fraction of blood shunted. bioavailability in patients with cirrhosis are de­ creased metabolising enzyme activity and intra- and Effects of Food and Other Drugs Influencing extrahepatic portacaval shunts. The bioavailability Organ Blood Flow of a drug in patients that have abnormal portaca­ Although a large number of reports describe the val shunts depends on both the extraction ratio (E) effect ofliver blood flow on the clearance of drugs, and the fraction of portal flow that is shunted few studies have measured concurrent changes in around the parenchymal tissue (Blaschke and the extent of first-pass metabolism. Several inves­ Rubin, 1979), according to the equation tigators have demonstrated that increasing hepatic blood flow by administering food or hydralazine F = SF + (I-SF) [1-(CL/Cm (Eq. 19), increases the bioavailability of highly extracted drugs (Mclean et aI., 1980; Melander et aI., 1977; where SF is the fraction of portal venous blood Schneck and Vary, 1983; Walle et aI., 1981). Both flow shunted directly to the vena cava. food (Melander et aI., 1977; Melander and Mc­ Lean, 1983; Schneck and Vary, 1983; Walle et aI., 1981) and hydralazine (McLean et aI., 1980) in­ 600 crease the relative bioavailability of propranolol. Walle and co-workers (1981) demonstrated that the AUC after oral administration of propranolol in 6 subjects increased from a mean of 221 ng/ml • h s~ during fasting to 332 ng/ml • h after a meal. How­ c: 400 ..,0 ever, the elimination half-life of propranolol was ~ C not altered. Ql I c:U 1.,- The physiological change produced by food or 0 lIT U II I II I hydralazine appears to be a transient increase in :2 II IT 200 I I I e I I the rate of perfusion of the splanchnic vascular sys­ Q. I 0 I Qi tem, reducing the fraction of drug extracted by the E liver while the drug is being absorbed (Melander E'" T (/) .,. and McLean, 1983). Increased hepatic blood flow 11:'" during absorption also probably explains the en­ 0 2 4 6 8 12 24 hancement of the bioavailability of dihydroergo­ Time (hours) tamine by glyceryl trinitrate observed in 4 patients by Bobik et a1. (1981). Fig. 6. Plasma concentration-time curves of metoprolol in ex­ tensive (e) and poor (0) hydroxylators of debrisoquine. The ver­ Protein Binding tical bars indicate the standard deviation. The plasma metopro- Clinical examples showing the effect of altered 101 concentrations after a single oral dose of 200mg metoprolol protein binding on bioavailability are lacking. tartrate were much higher in poor than in extensive hydroxy­ lators. [From Lennard et aI., New England Journal of Medicine However, the greater plasma concentrations of ox­ 307: 1558 (1982); reproduced with permission from the authors prenolol after oral administration to patients dur­ and publisher.j ing a mild illness, which increased the level of First-Pass Elimination 18

plasma proteins during the acute phase, is sugges­ provide a reservoir for unchanged drug in plasma. tive evidence of the phenomenon (Kendall et aI., The observation that very little propranolol glu­ 1979). Increased serum concentrations of propran­ curonide is generated after repeated intravenous olol have been found in a number of patients with doses supports their hypothesis. inflammatory diseases (Schneider and Bishop, 1982). Conversely, Toothaker and co-workers 2.4 Estimation of Bioavailability From a (1982) showed that the AUe after oral adminis­ Measured Response tration of hydrocortisone decreased as the dose increased. They suggested that this was due to A method to measure bioavailability without saturable binding of the drug to transcortin. measuring drug concentrations has been described by Porchet and Bircher (1982). These authors Non-Linear Kinetics measured, by digital plethysmography, the phar­ Many of the highly extracted drugs show dose­ macological effects of glyceryl trinitrate admini­ dependent and time-dependent bioavailability. stered both intravenously and orally. They used the Table I lists several drugs for which bioavailability area under the effect curve as a measure of the bio­ of a single oral dose increases as dose increases. availability. After oral administration virtually none These include 5-fluorouracil (Christophidis et aI., of the drug was bioavailable in healthy subjects by 1978), hydralazine (Shepherd et aI., 1982), lorcain­ this measurement. In patients with hepatic cirrho­ ide (Amery et aI., 1983; J ahnchen et aI., 1979), sis, however, the bioavailability varied between 0.15 phenacetin (Raaflaub and Duback, 1975), propran­ and 0.85. Those patients who had surgical porta­ olol (Shand and Rangno, 1972), and salicylamide. caval shunts had a greater bioavailability than those Very little of a Ig oral dose of salicylamide appears who did not. in the general circulation, but administration of a Winsor (1981) found that the bioavailability of 2g dose leads to an AVC that is 200 times greater sublingual ergotamine was similar to that of an than that seen after the Ig dose (Barr, 1969; Barr intramuscular dose by comparing the plethysmo­ et aI., 1973). graphic effects after each route of administration. The bioavailability of some drugs that are sub­ ject to extensive first-pass metabolism after admin­ 2.5 Bioavailability as a Measure of istration of a single dose increases when the drugs Hepatic Function are given repeatedly. This has been found with compounds such as lorcainide (Kates et aI., 1983), The bioavailability of many drugs usually sub­ metoprolol (Regardh and Johnsson, 1980), pro­ ject to extensive first-pass metabolism in normal pranolol (Evans and Shand, 1973), dextropropoxy­ subjects is increased in patients with hepatic cir­ phene (Inturrisi et aI., 1982), and verapamil (Kates rhosis. The use of the extent of drug extraction by et aI., 1981). The time dependency may not be ob­ the liver as a liver function test has been sum­ served in every subject (Bennett et aI., 1982) or marised by Branch (1982) and applied clinically by when the drugs are administered intravenously; for Huet et al. (1978) and Porchet and Bircher (1982). example, propranolol did not accumulate after re­ peated intravenous doses (Evans and Shand, 1973). 3. Conclusions The non-linearity is most probably due to satura­ tion of metabolism at the higher plasma drug con­ The clinical implications of first-pass elimina­ centrations achieved during repeated administra­ tion are manifold. Of the first-pass organs, the liver tion than after a single dose. In addition, Walle and has been the most extensively studied; relatively co-workers (1979) proposed that propranolol glu­ little information is available in humans on intes­ curonide, found in high concentrations during tinal or pulmonary metabolism or on the effects of administration of propranolol to steady-state, could altered organ blood flow and plasma protein bind- First-Pass Elimination 19

'Well-stirred' model 'Parallel tube' model

0.5 0.5 SF SF 0.4 0.4 0.3 0.3 ~0.3 0.3 :0 0.2 0.2 .!!! 'iii 0.2 > to 0.1 0 0.1 iii 0.1 0.1 0 0 0.0 0.0 12 24 36 48 60 2 4 6 8 10 12 a Intrinsic clearance (L/min) b Intrinsic clearance (L/min)

0.5 0.5 SF SF 0.4 0.4 0.3 0.3 ~0.3 0.2 0.3 :0 0.2 .!!! 'm 0.2 > 0.1 0.2 to 0.1 0 iii 0.1 0 0.1

0.0 0.0 5 1 2 3 4 5 C Blood flow (L/min) d Blood flow (LIm in)

0.5 0.5 SF SF 0.4 0.4 0.3 0.3 ~0.3 0.3 :B 0.2 0.2 ~ 0.2 0.2 > to 0.1 0 0.1 iii 0.1 0.1 0 0 0.0 0.0 0.2 0.4 0.6 0.8 1.0 0.4 0.6 0.8 1.0 e Fraction unbound Fraction unbound

Fig. 7. Shunting of the combined hepatic arterial and portal blood flows alters the expected effects on bioavailability of changes in intrinsic clearance, blood flow and unbound fraction. The expected effects of 10, 20, and 30% shunting of blood flow (SF) are simulated using equation 19 and the 'well-stirred' and 'parallel tube' models (see text). The intrinsic clearances for the two models are 60 and 12 Llmin, respectively, except in figs a and b. The total blood flow (shunted plus that through parenchymal tissue) is 1.5 Llmin, except in figs c and d. The unbound fraction is 1.0, except where indicated as a variable (figs e and f). First-Pass Elimination 20

ing on first-pass metabolism. These potentially im­ Assinder. D.F.: Chasseaud. L.F. and Taylor. T.: Plasma isosor­ portant areas require further exploration to broaden bide dinitrate concentrations in human subjects after admin­ our understanding of the clinically important istration of standard and sustained-release formulations. Journal of Pharmaceutical Sciences 66: 775-778 (1977). phenomenon of first-pass metabolism. Azarnoff. D.L.: Karim. A.: Lambert. H.; Boylan. J. and Schoen­ hardt. G.: Transdermal absorption: A unique opportunity for drug delivery: in Benet and Levy (Eds) Pharmacokinetics: A References Modern View (Plenum Publishing Corp. New York 1983). Bai. S.A. and Abramson. F.P.: Interactions of phenobarbital with Ablad. B.: Borg. K.O.: Johnsson. G., Regardh. c.-G. and Solvell. propranolol in the dog. I. Plasma protein binding. 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Rowland M.: Pharmacokinetics of lidocaine and its deethy­ European Journal of Clinical Pharmacology 15: 51-55 (1979). lated metabolite: Dose and time dependency studies in man. Alkalay. D.: Khemani. L.: Wagner Jr. W.E. and Bartlett. M.F.: Journal of Pharmacokinetics and Biopharmaceutics 10: 265- Sublingual and oral administration of methyltestosterone. A 281 (1982). comparison of drug bioavailability. Journal of Clinical Blackwell. E.W.; Briant. R.H.: Conolly. M.E.; Davies, D.S. and Pharmacology 13: 142-151 (1973). Dollery. C.T.: Metabolism of isoprenaline after aerosol and Alvan. G.: Borga. 0.: Lind. M.: Palmer. L. and Siwers. B.: First direct intrabronchial administration in man and dog. British pass hydroxylation of nortriptyline: Concentrations of parent Journal of Pharmacology 50: 581-591 (1973). drug and major metabolites in plasma. European Journal of Blaschke. T.F. and Rubin. P.c.: Hepatic first-pass metabolism in Clinical Pharmacology II: 219-224 (I 977a). liver disease. 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J.: Bruyneel. K. and Terryn. R.: Bio­ 2: 97-105 (1982). availability and saturation of the presystemic metabolism of Branch. R.A. and Shand. D.G.: Propranolol disposition in chronic oral lorcainide therapy initiated in three different dose regi­ liver disease: A physiological approach. Clinical Pharmaco­ mens. European Journal of Clinical Pharmacology 24: 517- kinetics I: 264-279 (1976). 519 (1983). Brauer. R.W.: Liver circulation and function. Physiological Re­ Andersson. K.-E.: Bergdahl. B.: Dencker. H. and Wettrell. G.: views 43: 115-213 (1963). Proscillaridin activity in portal and peripheral venous blood Brazzell. R.K.: Smith. R.B. and Kostenbauder. H.B.: Isolated per­ after oral administration to man. European Journal of Clinical fused rabbit lung as a model for intravascular and intrabron­ Pharmacology 11: 277-281 (1977). chial administration of bronchodilator drugs. I: Isoproterenol. Aquilonius. S.-M.: Eckernas. S.-A.: Hartvig. P.: Hultman. J.; Journal of Pharmaceutical Sciences 71: 1268-1278 (1982). Lindstrom. B. and Osterman. P.O.: A pharmacokinetic study Brunk, S.F. and Delle, ~1.: rv10rphinc metabolism in man. Clinical of neostigmine in man using gas chromatography-mass spec­ Pharmacology and Therapeutics. 16: 51-57 (1974). trometry. European Journal of Clinical Pharmacology 15: 367- Christophidis. N.: Vajda. FJ.E.: Lucas. I.: Drummer. 0.: Moon. 371 (1979) . W.J. and Louis. WJ.: Fluorouracil therapy in patients with .-\rmstrong. J.A.: Slaughter. S.E.: Marks. G.S. and Armstrong. P.W.: carcinoma of the large bowel: A pharmacakinetic comparison Rapid disappearance of nitroglycerin following incubation with of various rates and routes of administration. Clinical Phar­ human blood. Canadian Journal of Physiology and Pharma­ macokinetics 3: 330-336 (1978). cology 58: 459-462 (1980). Ckavcland. C.R. and Shand. D.G.: Effect of route of adminis- First-Pass Elimination 21

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The Laerdal Foundation for Acute Medicine

The Laerdal Foundation for Acute Medicine has been instituted with the purpose of providing financial support to research or development projects in the field of acute medicine, The foundation is governed by a board of apPOinted members from the follOWing organisations: The Faculty of Medicine of the University of Oslo, The Scandinavian Society of Anaesthesiologists, The Society of Critical Care Medicine (USA), and The Asmund S, Laerdal Company, Projects to be considered for support may include experimental or clinical studies, educational activities, practical improvements of patient transport, and publication of ideas and findings, Pre· hospital projects may be preferred. Deadlines for applications are bi·annually by Oct. 1 and April 1.

Application form and further information may be obtained from: Mr Olav Ekkje, The Manager, The Laerdal Foundation for Acute Medicine, P,O, Box 377, N·4001 Stavanger, Norway,