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The role of the lungs in drug distribution • 9 RC 4

Leiden University Medical Centre
Leiden, The Netherlands
Monday 31 May 1999 Amsterdam

The lungs are not usually considered important in the fate of drugs in the body since they contribute little to
total body mass and usually have a small metabolic capacity. Because of their strategic location between the
site of injection and the site of action, however, they can significantly influence drug concentrations
immediately after acute drug injection. This is particularly true for basic amines, which includes many drugs
used in anaesthesia, since first-pass lung uptake is large for these agents. First-pass lung uptake reduces
arterial concentrations immediately after injection, and limits the amount of drug available for distribution to
the effect site.
Educational goals
To review the effects the lungs have on blood concentrations immediately after injection and during the
mixing period; to discuss how these effects can be modelled, and explain the importance of uptake of drugs
in the lungs; to review those drugs that are retained in the lungs; and discuss how lung uptake can be
studied and how drug uptake in the lungs can be incorporated in pharmacological models.
The mixing period
It is often thought that blood concentrations are highest immediately after intravenous injection of a drug. It is
obvious that at some place in the body, near the site of injection, concentration must be high, but in the
arterial circulation the drug concentration will be zero during the first seconds after injection. The speed with
which the concentration will increase will depend on the cardiac output, the amount of blood between the site
of injection and the arterial point where the concentration is measured and on the uptake of the drug into the
lungs. Even in patients with a high cardiac output, central injection of the drug and no lung uptake, the drug
concentration will increase over several seconds to a maximum, then decrease to a first minimum and again
rise to a much smaller second peak (fig.1, open square symbols). After this, the concentration will follow the
well-known course of the multi-exponential decay curve. This first period of rapid peaks and troughs of drug
concentration is known as the mixing period.
The effects of mixing are observed during seconds to minutes after drug injection. How important is this to
the care of patients and how will an understanding of the phenomena affect patient treatment ? Mixing
phenomena are most important in those patients in whom the mixing is least, resulting in prolonged high
concentrations of anaesthetics, such as patients with a poor cardiac output, where greater drug
concentration can lead to a more pronounced cardiac depression or other haemodynamic side effectss
Better understanding of drug mixing could lead to an adaptation in the dosing of drugs, especially in those
patients in whom a poor mixing is anticipated.
The mixing period is affected by the blood volume of the central part of the circulation (the intrathoracic or
central blood volume), the cardiac output, the distribution of the cardiac output in the lungs and peripheral
tissues and lung uptake of drug. Several combinations of factors can lead to concentrations either greater or
smaller than normal during the mixing period. In general a low cardiac output will be associated with large
initial concentrations which will be maintained for longer (see fig.1). If the drug undergoes significant first-
pass uptake this will reduce initial concentrations. On the other hand if the lung uptake is decreased (by
competitive interaction by other drugs), the concentrations immediately after injection will be increased.
Apparently the lungs can play an important role during the mixing period.

Figure 1. The concentration-time curves after identical doses of indocyanine green (ICG) given during high
cardiac output (dashed line) and during normal cardiac output (grey line) in a sheep. The concentration-time
curve of propofol (black line), given simultaneously with ICG during normal cardiac output was corrected for
differences in dose. The differences in the ICG and propofol concentrations are explained by lung uptake.
Lung uptake
The lungs are important sites for uptake and metabolism of endogenous compounds, such as hormones and
prostaglandins [1,2]. Many drugs used in anaesthesia are also bound to the lungs (table 1) [3]. Usually the
binding is temporary, and drug is released from the lungs when pulmonary arterial concentrations decrease.
Metabolism in the lungs is rare and is usually seen only for endogenous substances which are used
therapeutically, such as n
oradrenaline and dopamine.
Table 1. Pulmonary uptake of drugs used in anaesthesia and other drugs
                    drug group                                          pulmonary
                    local anaesthetics: ropivacaine bupivacaine, low - moderate
                    mepivacaine, lidocaine
                    induction agents: thiopentone, propofol             low - high
                    muscle relaxants: curare, pancuronium, none
                    atracurium, rocuronium
                    opioids: morphine, alfentanil, pethidine, moderate - high
                    sufentanil, fentanyl
                    vasoactive drugs: noradrenaline, dopamine           moderate
                    non-anaesthetic    drugs:       imipramine,
                    chlorpromazine,     quinidine,      quinine,
                    verapamil,   propranolol,    nitrofurantoin,

There may be significant competition for binding sites in the lungs. Lung uptake of fentanyl may be
significantly less if the patient takes propranolol preoperatively [4]. Fentanyl on the other hand can under
certain circumstances decrease the pulmonary uptake of propofol [5]. The uptake of imipramine is decreased
by the anti-depressant clomipramine [6]. If there is competition for drug uptake in the lungs, this may cause
significantly greater arterial concentrations immediately after injection.
Drugs undergoing the highest pulmonary uptake share some characteristics: they are all highly lipophilic,
basic and often amines. The pulmonary uptake for neutral and acidic drugs is usually limited, although for
some of these drugs pulmonary uptake may be significant (e.g. propofol). Some speculate that the affinity of
basic amines for lung tissue is caused by their affinity for lysosomes, where they are trapped by ionization in
the acidic environment of the lysosome [7]. In addition, drugs can be bound to tissue elements, to proteins,
or diffuse into lipid structures. Studies of accumulation and release of drugs in isolated lung models show
that there are several depots in the lungs to which drugs bind, with different affinities and binding capacities
Lung uptake has been studied both in vitro and in vivo. In vitro methods often involve the use of isolated lung
models, in which the lungs of animals are included in a (re-circulatory) perfusion system. The isolated lung
model has been used extensively and has greatly added to the understanding of lung uptake [9]. The results
of these studies, however, should be extrapolated with caution to man, because important differences in lung
uptake may exist between species. In vivo lung uptake can be studied by an indicator dilution method, in
which the first-pass retention is calculated by comparison of the drug concentration curve to that of an
indicator not undergoing pulmonary uptake. Clearly the double indicator dilution method is limited to the first-
pass period. The period beyond first-pass can be studied by mass balance methods, compartmental
analysis, system dynamics and recirculatory modelling. Most of these methods, except recirculatory
modelling, require measurement of both arterial and pulmonary arterial concentrations, which limits their
Modelling lung uptake
The mixing period, although highly relevant to anaesthesiologists, is poorly described by the compartmental
models commonly used in research, and also used for controlling infusion pumps, such as the Diprifusor.
Because lung uptake can have an important influence on the concentrations immediately after injection, it
would be relevant to try to incorporate this phenomenon in pharmacological modelling. Lung uptake is
difficult to incorporate into the compartmental models, since these models assume immediate and complete
mixing. Moreover, in most studies of drug kinetics using compartmental models, sampling commences only
after 1-2 minutes after injection, that is after the period of initial mixing. The concentration at time zero on
which the calculation of some pharmacokinetic parameters is based is therefore not an observed
concentration. The concentration is obtained by back-extrapolation to zero of the concentration-time
relationship and is thus a calculated value. This leads to discrepancies with the actual concentrations
immediately after injection and will affect in particular the calculated size of the central volume of distribution.
Although speculative, it is likely that significant lung uptake will further affect the size of both the central
volume of distribution of the drug and, to a lesser extend, the volume of the peripheral compartment (V2).
If both arterial and pulmonary arterial samples are available, lung uptake may be modelled using a
physiological model [10] or by system analysis [11]. These models can predict the arterial concentrations if
pulmonary arterial concentrations are known, and provide information on the distribution volume in the lungs.
However these models have not been integrated, into a complete model of the body and thus are of limited
value to the clinician.
Integrated modelling of pulmonary uptake is possible with physiological models and recirculatory models.
Physiological models are frequently used for research in animals. The results may to some extent be scaled
up to humans [12], but may have intrinsic weaknesses if the kinetic behaviour of the drug differs between
species. Physiological models cannot be fully validated in patients and volunteers, since they need precise
information on organ volumes, composition and blood flows. Pulmonary uptake can also be modelled by
recirculatory models, together with the other phenomena taking place during the mixing phase [13-15]. The
advantages of these models are that they describe lung uptake beyond the period of first-pass, that the
mixing period can be fully modelled, and that only arterial samples are required. Using this model for the
study of alfentanil in pigs, we estimated the pulmonary volume of distribution of alfentanil, which agreed with
the volumes found with compartmental modelling and system dynamics analysis in similar pigs [16]. The
model used in this study is shown in fig. 2 and is very similar to the models used by Henthorn and coworkers

For many drugs used in anaesthesia the lung is a site of first-pass uptake when the drug is given
intravenously. A significant first-pass uptake will decrease the arterial concentrations, in particular during the
initial mixing period. This effect of lung uptake, together with effects of blood volume and cardiac output on
the initial concentrations immediately after injection are not predicted by compartmental models.
Physiological models and in particular recirculatory models are better capable of predicting the course of the
concentrations in the mixing period.

1.       Bend J, Serabjet-Singh C, Philpot RM. The pulmonary uptake, accumulation, and metabolism of
xenobiotics. American Review of Pharmacology and Toxicology 1985;25:97-125.
2.       Ryan US, Grantham CJ. Metabolism of endogenous and xenobiotic substances by pulmonary
vascular endothelial cells. Pharmacology and Therapeutics 1989;42: 235-250.
3.       Roerig DL, Ahlf SB, Dawson CA, Linehan JH, Kampine JP. First pass uptake in the human lung of
drugs used during anaesthesia. Advances in Pharmacology 1994;31: 531-549.
4.       Roerig DL, Kotrly KJ, Ahlf SB, Dawson CA, Kampine JP. Effect of propranolol on first pass uptake of
fentanyl in the human and rat lung. Anesthesiology 1989;71: 62-68.
5.       Matot I, Neely CF, Katz RY, Marshall BE. Fentanyl and propofol uptake by the lung: effect of time
between injections. Acta Anaesthesiologica Scandinavica. 1994;38: 711-715.
6.       Suhara T, Sudo Y, Yoshida K, et al. Lung as reservoir for antidepressants in pharmacokinetic drug
interactions. Lancet 1998;351: 332-335.
7.       MacIntyre AC, Cutler DJ. The potential role of lysosomes in tissue distribution of weak bases.
Biopharmaceutics and Drug Disposition 1988;9: 513-526.
8.       Philpot RM, Anderson MW, Eling TE. Uptake, accumulation, and metabolism of chemicals in the
lung. In: Metabolic functions of the lungs. Bahkle YS, Vane JR. eds. Marcel Dekker, New York, 1977;123-
9.       Bend JR. Isolated perfused lungs in drug disposition studies. In: Topics in Pharmaceutical Sciences
1987. Breimer DD, Speiser P. eds. Elseviers Science Publishers, Amsterdam, 1987;235-246.
10.      Boer F, Olofsen E, Bovill JG, Burm AGL, Hak A, Geerts M. Pulmonary uptake of sufentanil during
and after constant rate infusion. British Journal of Anaesthesia 1996;76: 203-208.
11.      Boer F, Hoeft A, Scholz M, Burm AGL, Bovill JG, Hak A. Pulmonary distribution of alfentanil and
sufentanil studied with system dynamics analysis. Journal of Pharmacokinetics & Biopharmaceutics 1996;
24: 197-218.
12.      Bjorkman S, Wada DR, Stanski DR, Ebling WF. Comparative physiological pharmacokinetics of
fentanyl and alfentanil in rats and humans based on parametric single-tissue models. Journal of
Pharmacokinetics & Biopharmaceutics 1994;22:381-410.
13.      Krejcie TC, Avram MJ, Gentry WB, Niemann CU, Janowski MP, Henthorn TK. A recirculatory model
of the pulmonary uptake and pharmacokinetics of lidocaine based on analysis of arterial and mixed venous
data from dogs. Journal of Pharmacokinetics & Biopharmaceutics 1997;25: 169-190.
14.      Krejcie TC, Henthorn TK, Shanks CA, Avram MJ. A recirculatory pharmacokinetic model describing
the circulatory mixing, tissue distribution and elimination of antipyrine in dogs. Journal of Pharmacology and
Experimental Therapeutics 1994;269: 609-616.

15.    Henthorn TK, Avram MJ, Krejcie TC, Shanks CA, Asada A, Kaczynski DA. Minimal compartmental
model of circulatory mixing of indocyanine green. American Journal of Physiology 1992;262: H903-H910.
16.    Kuipers, JA, Boer F, Olofsen E, Oliemans W, Bovill JG, Burm, A G L. Recirculatory and
compartmental pharmacokinetics of alfentanil in pigs: the influence of cardiac output. Anesthesiology,
accepted for publication.

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