Summary
`
`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
`
`First-pass elimination takes place when a drug is metabolised between its site of admin(cid:173)
`istration and the site of sampling for measurement of drug concentration. Clinically, first(cid:173)
`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(cid:173)
`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(cid:173)
`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 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 biG(cid:173)
`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(cid:173)
`pendent of concentration and time. The predictions of the models are similar when bio(cid:173)
`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(cid:173)
`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(cid:173)
`tabolite concentration-time profiles after oral and parenteral administration. After an oral
`
`1
`
`

`
`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(cid:173)
`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(cid:173)
`dependent differences in pharmacological and toxicological responses to a given concen(cid:173)
`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(cid:173)
`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(cid:173)
`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. Rela(cid:173)
`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(cid:173)
`tabolism. These potentially important areas require further exploration to broaden our
`understanding of the clinically important phenomenon of first-pass metabolism.
`
`In clinical practice, drug concentrations are
`measured in peripheral venous blood or plasma.
`When drug is eliminated between the site of
`administration and the site of sampling for meas(cid:173)
`urement, first-pass elimination of the drug has oc(cid:173)
`curred. This elimination is usually assumed to
`occur via metabolism. First-pass metabolism in the
`gastrointestinal tract and liver of drugs admini(cid:173)
`stered orally has been studied most extensively and
`is of importance because most drugs are admini(cid:173)
`stered orally. First-pass metabolism is important
`clinically when the fraction of the dose that escapes
`loss at these metabolic sites is small and variable.
`In this review, concepts basic to the process of first(cid:173)
`pass metabolism are examined. The implications
`of first-pass metabolism on the therapeutic use of
`
`drugs are emphasised and illustrated by clinically
`important examples whenever possible.
`
`1. Basic Concepts
`l.l Organs Involved
`
`The liver is usually assumed to be the major site
`of first-pass metabolism of a drug administered
`orally. Other potential sites after oral administra(cid:173)
`tion are the gastrointestinal flora and mucosa,
`blood, vascular endothelium, lungs, and the limb
`in which venous samples are taken. It is difficult
`to establish the exact site of drug metabolism after
`oral administration by sampling only blood. Po(cid:173)
`tential sites can be identified in vitro in isolated
`whole organs, tissue slices, homogenates, or blood
`
`2
`
`

`
`First-Pass Elimination
`
`3
`
`enzyme preparations. In animals, identification of
`involvement of the intestine and liver can be
`achieved by comparing the areas under the plasma
`concentration-time curve (AVC) after intravenous,
`oral and intraportal drug administration (Iwamoto
`and Klaassen, 1977a,b; Rheingold et aI., 1982;
`Rowland, 1972). Similar manipulations of route of
`administration can identify other potential sites of
`metabolism, such as the lungs (Brazzell et aI., 1982).
`In humans, the portal vein has been catheter(cid:173)
`ised to study the first-pass metabolism in the in(cid:173)
`testine of oral doses of flurazepam (Mahon et aI.,
`1977) and proscillaridin (Andersson et aI., 1977).
`The kinetic behaviour of intraperitoneal, intraven(cid:173)
`ous (Collins et aI., 1980), or intrahepatic arterial
`doses (Ensminger et aI., 1978) of 5-fluorouracil has
`also been examined. Shand and Rangno (1972), by
`studying a patient who had a surgical portacaval
`anastamosis, showed that the intestine does not
`metaboIise propranolol. In other studies, the first(cid:173)
`pass uptake and elimination of compounds by the
`lungs have been studied in patients undergoing
`routine cardiac catheterisation (Geddes et aI., 1979;
`Jose et aI., 1976). Woodcock and co-workers (1981)
`directly measured the hepatic extraction of vera(cid:173)
`pamil in cardiac patients.
`
`1.2 Concept of Bioavailability
`
`BioavaiiabiJity - defined as the ratio of the AVCs
`(corrected for dose if necessary) after extra- and
`intravascular drug administration (Tozer, 1979) -
`is often used as a measure of the extent of first(cid:173)
`pass metabolism. When several sites of first-pass
`metabolism are in series, the availability of the drug
`can be viewed as the product of the fractions of
`drug entering the tissue that escape loss in each
`successive tissue. Thus, the product (Foral) for an
`orally administered drug that is metabolised in the
`gastrointestinal lumen (G), the intestinal wall (I),
`liver (L), lung (Lu), arm (A), and blood and endo(cid:173)
`thelial linings or the vascular system (B) is
`
`(Eq. 1)
`
`arm and sampled in the other, the product is
`Fiv = FLu • FA • FB
`
`(Eq. 2).
`
`Combining equations 1 and 2 results in
`
`(Eq. 3).
`
`By definition, Fiv is conventionally assigned a value
`of unity. Thus, the bioavailability of an orally ad(cid:173)
`ministered drug is then the product of the fractions
`entering the irttestinal wall and escaping loss in the
`intestine and liver. It should be clear from equa(cid:173)
`tion 2 that the assignment of unity to Fiv is arbi(cid:173)
`trary. Consequently, the application of the term
`'absolute bioavailability' to the value obtained from
`comparison with intravenous administration may
`be inappropriate when elimination occurs in the
`lungs, arm, blood or vascular endothelium.
`
`1.3 Pharmacokinetic Considerations
`
`When the liver is the sole site of loss,
`
`Foral = 1 - E
`
`(Eq.4),
`
`where E is the extraction ratio, i.e. the fraction of
`drug entering the liver that is eliminated by the
`organ. Vnder steady-state conditions, the rate of
`extraction of drug by the liver [the product of the
`hepatic (H) blood clearance (CLHB) and the con(cid:173)
`centration of drug in blood (CB)] equals the rate of
`presentation of the drug to the liver [the product
`of liver blood flow (em) and CB]. Consequently,
`the extraction r!itio is, by definition:
`E = CLHB' CB
`QH' CB
`
`(Eq. 5).
`
`Therefore,
`Foral = 1 -
`
`(CLHB/QH)
`
`(Eq. 6).
`
`When intravenously (iv) administered in one
`
`Equation 6 indicates that the relative changes in
`the two pharmacokinetic parameters CLHB and F oral
`
`3
`
`

`
`First-Pass Elimination
`
`4
`
`will not be the same. For example, if clearance de(cid:173)
`creases from 99 to 97% of blood flow, a 2% de(cid:173)
`crease, the bioavailability increases from 0.01 to
`0.03, a 200% increase.
`Equations 5 and 6 use hepatic clearance calcu(cid:173)
`lated from drug concentrations in whole blood, CB.
`However, most clinical pharmacokinetic informa(cid:173)
`tion has been obtained from plasma drug concen(cid:173)
`trations. Plasma flow and plasma drug concentra(cid:173)
`tion of drug (Cp) cannot be substituted into
`equation 5 unless the drug is confined to plasma
`(Rowland, 1972), in which case Cp = CB • [1 -
`Haematocrit (Hct»). In all other cases the blood-to(cid:173)
`plasma concentration ratio must be determined.
`The relationship between blood and plasma drug
`concentrations depends on the haematocrit and the
`relative affinities of the drug for blood cells and
`plasma proteins. This conclusion can be derived
`from the principles of mass balance, in that
`
`Amount
`in blood
`
`==
`
`Amount
`in plasma
`
`V BC • CBC
`+ I
`i
`Amount in
`blood cells
`
`(Eq. 7),
`
`where VB, V p, and V Be are the volumes of blood,
`plasma, and red blood cells, respectively, and CB,
`Cp, and eBC are the concentrations of drug in these
`respective volumes; V Be/V B is the haematocrit and
`Vp/VB = I - Hct. Dividing by (VB· Cp) gives
`
`CB
`-
`Cp
`
`.
`
`CBC
`= (I-Hct) + Hct· -
`Cp
`
`(Eq. 8).
`
`The ratio ofbloodlplasma drug concentrations, CBI
`Cp, lies between the limits of(l - Hct) and a larger
`value determined by the relative affinities of drug
`for blood cells and for plasma proteins.
`Clearances based on drug in whole blood (CLB)
`and in plasma (CLp) are related by
`
`(Eq. 9).
`
`This relationship is obtained from the definition
`of clearance values, that is, rate of elimination =
`CLp • Cp = CLB • CB'
`Whether or not a drug undergoes extensive first(cid:173)
`pass elimination can be anticipated from plasma
`
`data when 4 parameters are known: the ratio of
`blood-to-plasma concentrations; plasma clearance
`(CLp); fraction of drug in the body that is excreted
`unchanged in urine (fe); and liver blood flow. Blood
`clearance (CLB) is calculated first using equation 9.
`The fraction undergoing non-renal elimination
`is (1 -
`fe)' If the liver is assumed to be the sole
`non-renal organ of elimination, the hepatic blood
`clearance (CLBB) is then
`
`(Eq. 10).
`
`By substituting equations 9 and 10 into equation
`6, bioavailability becomes
`
`Foral = I -
`
`(Eq. 11).
`
`(l-fe)· CLp
`QB • CB/Cp
`The importance of knowing the blood-to-plasma
`drug concentration ratio is illustrated by the. fol(cid:173)
`lowing example. Consider 2 drugs with plasma
`clearance values of 1500 ml/min, negligible excre(cid:173)
`tion in urine, and blood-to-plasma concentration
`ratios of 1.1/1 and 100/1. Assuming an hepatic
`blood flow of 1500 ml/min, the oral bioavailabil(cid:173)
`ities of the 2 compounds calculated from equation
`11 are 0.09 and 0.99, respectively. These values are
`greatly ditTerent even though the plasma clearances
`are identical.
`
`1.4 Non-Linear First-Pass Metabolism
`
`The bioavailability of somt! compounds changes
`with dose. For example, bioavailabilities of ribo(cid:173)
`flavine (vitamin B2) [Levy and Jusko, 1966] and
`cyanocobalamin (vitamin Bd (Diem, 1962) de(cid:173)
`crease with increasing doses because of capacity(cid:173)
`limited transport. Conversely, the bioavailability
`of propranolol increases as dose increases (Shand
`and Rangno, 1972) because of limited capacity of
`the metabolising hepatic enzymes (Walle et aI.,
`1981). Theoretically, saturable binding of drug to
`plasma proteins could also produce non-linear first(cid:173)
`pass metabolism.
`First-pass metabolism after oral doses may be
`non-linear when metabolism after intravenous
`doses, administered on separate occasions, is not.
`
`4
`
`

`
`First-Pass Elimination
`
`5
`
`The reason lies in the difference between the con(cid:173)
`centration of drug entering the liver after each route
`of administration. Consider the oral administra(cid:173)
`tion of a drug eliminated only in the liver and with
`I-compartment characteristics. Assuming that the
`absorption into the portal vein is first-order, the
`initial rate of input of drug is ka • dose, where ka
`is the absorption rate constant. The initial rate of
`entry of drug into the liver is Q,v • Cpv, where
`Q,v is the portal blood flow and Cpv is the drug
`concentration in the portal vein blood as it enters
`the liver. Anatomically, the hepatic artery adds to
`portal blood flow. So, the rate of entry of drug may
`be expressed as ~ • CA where ~ is the total liver
`blood flow and CA is the concentration of drug
`measured after dilution by hepatic arterial blood.
`The initial rate of presentation of drug to the liver
`after a single oral dose is
`
`(Eq. 12).
`
`On rearrangement, the initial concentration enter(cid:173)
`ing the liver is
`
`(Eq. 13).
`
`After a single intravenous dose (iv), the corre(cid:173)
`sponding concentration is
`
`(Eq. 14),
`
`where V d is the apparent volume of distribution
`of the drug. If the oral and intravenous doses are
`the same, the ratio of these resulting concentra(cid:173)
`tions is
`
`tration ratio is large only if absorption is fast. Thus,
`the potential for non-linear first-pass metabolism
`exists when absorption is fast and/or the apparent
`volume of distribution is large.
`Figure 1 was simulated when the oral and intra(cid:173)
`venous doses were given on separate occasions. It
`is important to note that if an intravenous radio(cid:173)
`labelled tracer dose is given concurrently with an
`oral dose, the intravenous kinetics will reflect the
`non-linear first-pass metabolism during absorp(cid:173)
`tion, but may be non-linear over too short a time
`to be measurable.
`
`Influence of Dosage Form
`The dosage form of a drug can have an impact
`on non-linear first-pass metabolism. From the ar(cid:173)
`gument above, the concentration entering the liver
`depends on the rate of entry of drug into the portal
`vein. The slower the rate of release from a dosage
`form, the lower the concentration entering the liver.
`Thus, slow absorption from a sustained release
`
`\
`
`Vd(L)
`
`~
`
`CA.oral
`
`CA.iv
`
`(Eq. 15).
`
`Absorption half-life (minutes)
`
`Figure 1, derived from equation 15, illustrates
`how this ratio varies with the absorption half-life
`(O.693/ka) and the apparent volume of distribution
`(V d). If V d is large (> 200L) the initial concentra(cid:173)
`tion entering the liver after an oral dose is much
`greater than that after an equivalent intravenous
`dose at all of the absorption half-lives shown. On
`the other hand, if V d is small « SOL) the concen-
`
`Fig. 1. The ratio of the initial drug concentrations entering the
`liver after an oral dose and after the same intravenous dose
`varies with the absorption half· life and the apparent volume of
`distribution (Vd). The shorter the absorption half-life and the larger
`the apparent volume of distribution, the greater the ratiO. This
`figure was obtained by simulation of equation 15; the absorption
`half-life = O.693/ka . The following assumptions were made: dis(cid:173)
`tribution is instantaneous, absorption and elimination are first(cid:173)
`order processes, and the liver is the sole site of elimination.
`
`5
`
`

`
`First-Pass Elimination
`
`6
`
`dosage form may not show non-linear bioavaila(cid:173)
`bility, whereas rapid absorption of the same dose
`given in solution or a rapidly dissolving dosage
`form may show non-linear bioavailability. This
`probably explains the much greater apparent bio(cid:173)
`availability of salicylamide given as a suspension
`than as a solid dosage form (fleckenstein et ai.,
`1976).
`
`1.5 Physiological Variables Involved in
`First-Pass Metabolism
`
`The extent of first-pass metabolism in the liver
`and intestinal wall depends on a number of phys(cid:173)
`iological factors. The major ones are enzyme ac(cid:173)
`tivity, plasma protein and blood cell binding, blood
`flow, and gastrointestinal motility.
`
`1.5.1 Hepatic First-Pass Metabolism
`
`Enzyme Activity
`The inherent enzyme activity is usually the most
`important determinant of the extent of first-pass
`metabolism. The activity is commonly expressed
`in terms of the Michaelis-Menten parameters, Vm
`(the maximum rate of metabolism) and Km (the
`concentration at which the rate of metabolism is
`Vm/2). The value of Vm is related to amount of
`enzyme present and the capacity per mole of en(cid:173)
`zyme. In classic enzyme kinetics
`Vm· S
`Km+S
`
`Rate of metabolism =
`
`(Eq. 16),
`
`models used to predict the dependence of F on flow
`are discussed in section 1.6.
`
`Plasma Protein Binding
`Increasing plasma protein binding increases
`bioavailability; the converse is also true. However,
`the extent of the changes is difficult to predict
`quantitatively. Two models used to predict the de(cid:173)
`pendence of bioavailability on protein binding are
`discussed in section 1.6; these models differ mark(cid:173)
`edly in their estimates of the degree of change. The
`theoretical predictions are difficult to verify in hu(cid:173)
`mans because factors that alter plasma protein
`binding usually also alter other physiological vari(cid:173)
`ables such as blood flow and hepatic enzyme ac(cid:173)
`tivity. For example, phenobarbitone increases the
`plasma protein binding of propranolol in the dog
`but also enhances hepatic metabolising enzyme ac(cid:173)
`tivity and probably increases liver blood flow (Bai
`and Abramson, 1982; Vu et ai., 1983).
`
`Gastrointestinal Motility
`Gastric emptying and intestinal motility affect
`the rate of absorption of drugs and may also influ(cid:173)
`ence the extent of first-pass metabolism in the liver
`if the metabolism is non-linear. Increasing gas(cid:173)
`trointestinal motility may increase the rate of de(cid:173)
`livery of drug to the liver. If metabolism is non(cid:173)
`linear, this increased delivery will result in in(cid:173)
`creased bioavailability. The converse is anticipated
`when gastric emptying is delayed or intestinal mo(cid:173)
`tility is diminished.
`
`where S is the substrate concentration. Saturability
`or non-linearity occurs when S approaches and ex(cid:173)
`ceeds the value of Km; the rate then approaches
`Vm. The relationship in equation 16 often ade(cid:173)
`quately explains the kinetics of drug metabolism
`in vitro, but there are many additional factors in
`vivo that must be considered, including blood flow
`and the supply of co-factors.
`
`Blood flow
`Increasing blood flow increases bioavailability;
`the converse is also true. The extent of the change
`depends on the extraction ratio of the drug. Two
`
`1.5.2 First-Pass Metabolism in the
`Gastrointestinal Mucosa
`When the primary site of first-pass metabolism
`is the intestinal mucosa, the expected direction of
`the effects of altered enzyme activity, blood flow,
`and plasma protein binding on bioavailability are
`similar to those for the liver. However, the reasons
`for the relationships are different. In the intestinal
`mucosa, drug diffuses to the enzymes, and drug
`and metabolites are removed by the blood. One
`might speculate that blood acts as a sink. As a con(cid:173)
`sequence, when blood flow is increased, drug may
`be removed from the mucosa to a greater extent,
`
`6
`
`

`
`First-Pass Elimination
`
`7
`
`'Well-stirred' model
`
`'Parallel tube' model
`
`0.20
`
`0.16
`
`~ 0.12
`is
`~ 0.08
`
`> '" iij 0.04
`
`0.00
`
`a
`
`0.20
`
`0.16
`
`~ 0.12
`is
`.!!!
`'iii
`
`> '" 0
`CD
`
`Intrinsic clearance (L/min)
`
`C
`
`Blood flow (L/min)
`
`0.20
`
`0,16
`
`~0,12
`
`is '" ~ 0.08
`> '" o
`iii 0.04
`
`~"
`
`0.06
`
`Intrinsic clearance (L/min)
`
`Blood flow (L/min)
`
`0.20
`
`0.16
`
`0.12
`
`0.08
`
`0.04
`
`0.00
`
`b
`
`0.20
`
`0.16
`
`0.12
`
`0.08
`
`0.04
`
`0.00
`
`d
`
`0.20
`
`0.12
`
`0.04
`
`e
`
`Fraction unbound
`
`o.oo-~=-""'~~~""'"":~~
`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.
`
`7
`
`

`
`First-Pass Elimination
`
`8
`
`resulting in increased bioavailability. Decreased
`plasma protein binding may reduce the ability of
`blood to pick up the drug, thus reducing bioavail(cid:173)
`ability. The potential effects of altering gastroin(cid:173)
`testinal motility are unpredictable.
`
`1.6 Models of First-Pass Metabolism
`in the Liver
`
`Models that describe dependence of bioavaila(cid:173)
`bility on changes in enzyme activity, blood flow,
`and plasma protein and blood cell binding have
`been developed. Two that have been applied widely
`are the 'well-stirred' model (Rowland et aI., 1973;
`Wilkinson and Shand, 1975) and the 'parallel tube'
`model (Brauer, 1963; Winkler et aI., 1973, 1974).
`In a 'well-stirred' model, the liver is treated
`as a well-stirred container in which the unbound
`drug concentration in hepatic venous blood is the
`concentration available to the metabolising en(cid:173)
`zyme(s). In this model, the fraction of incoming
`drug that escapes metabolism in the liver (F d is
`QH
`QH + CLint' fUB
`where ~ is hepatic blood flow, CLint is the in(cid:173)
`trinsic clearance, which relates the rate of metab(cid:173)
`olism to the unbound drug concentration in he(cid:173)
`patic venous blood, and fUB is the unbound fraction
`of drug in blood.
`In the 'parallel tube' model, the liver is treated
`as a series of equivalent parallel tubes that have
`constant enzyme activity along the length of each
`tube. Drug concentration in perfusing blood de(cid:173)
`creases along the tube. The fraction escaping loss
`in this model is
`
`(Eq. 17),
`
`(Eq. 18),
`where fUB and Q; are as defined above, and CLint
`relates the rate of metabolism to the average un(cid:173)
`bound concentration within the tube.
`These models are similar in their predictions
`when bioavailability is large but differ dramatically
`when bioavailability is small. Figure 2 shows how
`bioavailability changes with enzyme activity, blood
`
`flow, and plasma protein binding. Note that the
`'parallel tube' model always predicts a much greater
`change in F than the 'well-stirred' model for a given
`change in intrinsic clearance, blood flow, or frac(cid:173)
`tion unbound.
`Because these two models summarise quanti(cid:173)
`tatively the expected relationships between bio(cid:173)
`availability and changes in enzyme activity, blood
`flow and protein binding, they may be useful.
`However, they must be tested for thdr validity, and
`drugs with low bioavailability due to extensive first(cid:173)
`pass hepatic metabolism provide tools for doing
`so. Similarities and differences between the two
`models have been examined (Ahmad et aI., 1983;
`Pang and Rowland, I 977a,b,c). The 'well-stirred'
`model describes the hepatic elimination of pro(cid:173)
`pranolol (Branch and Shand, 1976) and lignocaine
`(Pang and Rowland, 1977b,c). The 'parallel tube'
`model describes the elimination of galactose in the
`perfused pig liver (Keiding et aI., 1976; Keiding and
`Chiarantini, 1978).
`Without modification, these models are ex(cid:173)
`pected to be inadequate to predict bioavailability
`in vivo when metabolism is non-linear, hepatic
`blood flow is shunted, drug undergoes enterohe(cid:173)
`patic recycling, or metabolism occurs in other first(cid:173)
`pass organs.
`
`2. Clinical Consequences of First-Pass
`Elimination
`2.1 Route of Administration and
`Bioavailability
`
`2.1.1 Oral Administration
`Many clinically important drugs undergo con(cid:173)
`siderable first-pass metabolism after an oral dose.
`The characteristics of selected drugs that undergo
`50% or more first-pass metabolism after an oral
`dose are presented in table I. Although many of
`the drugs listed in the table undergo first-pass me(cid:173)
`tabolism in the liver, some are metabolised by in(cid:173)
`testinal flora or mucosa. Drugs metabolised in the
`intestine include levodopa, flurazepam, isoprena(cid:173)
`line, ~-methyldigoxin, oestrogen, phenacetin and
`salicylamide (George, 1981), and proscillaridin
`(Andersson et ai., 1977).
`
`8
`
`

`
`First-Pass Elimination
`
`9
`
`The major therapeutic implication of extensive
`first-pass metabolism is that much larger oral than
`intravenous doses are required to achieve equiv(cid:173)
`alent plasma concentrations. For some of these
`drugs, the extent of first-pass metabolism, at least
`in part, precludes their use as oral agents. Com(cid:173)
`pounds in this category include lignocaine, nalox(cid:173)
`one, glyceryl trinitrate (nitroglycerin), and dihy(cid:173)
`droergotamine. Despite its low bioavailability,
`dihydroergotamine can be used orally to treat some
`patients with orthostatic hypotension, probably be(cid:173)
`cause they have greater sensitivity to the drug's
`vasoconstricting effects (Bobik et aI., 1981).
`The lack of pharmacological activity and bio(cid:173)
`availability of oral naloxone (Fishman et aI., 1973)
`has been utilised recently in a novel formulation
`of pentazocine tablets (Talwin® Nx, package insert,
`Winthrop Laboratories, New York) to prevent their
`injection intravenously by drug abusers (Poklis and
`Mackell, 1982). The combination of pentazocine
`and naloxone taken orally has the desired analgesic
`effect. In contrast, no effect is experienced when
`the tablets are crushed and injected intravenously
`because the naloxone, now fully bioavailable, blocks
`the pentazocine effect.
`
`2.1.2 Transdermal Delivery
`Clinicians apply drugs topically to treat various
`skin diseases but have only recently begun to use
`the skin to reach the general circulation. Topical
`dosage forms of glyceryl trinitrate provide an ex(cid:173)
`ample of this latter use. Glyceryl trinitrate has a
`short elimination half-life (1.3 to 3.8 minutes), a
`large apparent volume of distribution (1.7 to 5.2
`L/kg), and a high plasma clearance (0.3 to 1.0 L/
`min/kg) [McNitT et aI., 1981]. Transdermal deliv(cid:173)
`ery of glyceryl trinitrate has been developed, in part,
`to avoid hepatic first-pass metabolism of an oral
`dose. However, the transdermally delivered drug
`still undergoes some first-pass metabolism in the
`skin (Wester et aI., 1981), blood, and vascular
`endothelium (Armstrong et aI., 1980; Fung and
`Kamiya, 1981; Wu et aI., 1981). The volume of
`blood and surface area of the vascular endothelium
`to which the drug is exposed are among the factors
`that dictate the extent of metabolism between the
`
`site of administration and the site of blood sam(cid:173)
`pling. When 2% glyceryl trinitrate ointment was
`applied to the skin of the left wrist, contralateral
`antecubital venous blood concentrations of gly(cid:173)
`ceryl trinitrate did not exceed 0.1 ng/ml (AzarnotT
`et aI., 1983). In contrast, blood from ipsilateral veins
`had mean peak concentrations of 12 ng/ml. These
`site-related ditTerences in apparent bioavailability
`are reflected by significant differences in the re(cid:173)
`sponse of normal subjects to glyceryl trinitrate when
`the same doses are applied to ditTerent body sites
`(Hansen et aI., 1979).
`
`2.1.3 Inhalation and Buccal Administration
`Societies have known for hundreds of years that
`inhalation of nicotine or opium produces the de(cid:173)
`sired effect, whereas oral administration either does
`not or requires much larger doses. Drugs given by
`inhalation include sympathomimetic agents and
`corticosteroids used to treat asthma. These are given
`by inhalation to deliver the drug directly to their
`sites of action. Some do undergo extensive first(cid:173)
`pass metabolism after oral administration, e.g. sal(cid:173)
`butamol (Evans et aI., 1973) and isoprenaline
`(Blackwell et aI., 1973). Because the lung plays only
`a small role in the biotransformation of these com(cid:173)
`pounds, inhalation of these drugs might be ex(cid:173)
`pected to give the metabolite pattern expected of
`an intravenous dose. However, after administra(cid:173)
`tion of 3H-salbutamol by inhalation of an aerosol
`form, 55% of the radioactivity in urine over the
`first 24 hours was recovered as metabolite, similar
`to the 61 % after oral administration; in contrast
`only 27% was recovered as metabolite after intra(cid:173)
`venous administration (Evans et aI., 1973). Inhaled
`isoprenaline also behaves pharmacokinetically like
`an oral dose, with the majority of the drug under(cid:173)
`going sulphation - not O-demethylation, the fate of
`an intravenous dose (Blackwell et aI., 1973). These
`data indicate that most of the drug inhaled as an
`aerosol is eventually swallowed. Presumably, most
`of the aerosol is trapped in the upper airway be(cid:173)
`cause of the large droplet size.
`Sublingual or buccal administration of a drug
`may produce blood concentrations similar to those
`of an equivalent intravenous dose. This similarity
`
`9
`
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`(1979); Pond et al. (1980)
`Ehrnebo et al. (1977); Neal et al.
`
`with cancer
`F determined in patients Brunk and Delle (197