Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 6–11.
Review article: albumin as a drug—biological effects of albumin
unrelated to oncotic pressure
T. W. EV ANS
Department of Intensive Care Medicine, Imperial College of Science, Technology & Medicine, Clinical Director of ICU,
Royal Brompton Hospital, London
SUMMARY
Albumin is the main determinant of plasma oncotic
pressure and it plays a pivotal role in modulating the
distribution of fluids between compartments. Moreover,
it has many other biological properties which may be
important not only for its physiological actions but also
STRUCTURE, SYNTHESIS, CATABOLISM AND
DISTRIBUTION
Human albumin constitutes some 50% of the protein
present in the plasma of normal healthy individuals. It is
a 66 kDa protein, which is small relative to other
plasma proteins. Albumin is highly soluble and of
elliptical shape with a low intrinsic viscosity. Albumin is
a very stable protein, although more than 50 slight
variants of the 585-amino acid sequence that comprises
human albumin have been described. These are termed
allo-albumins, and can co-exist in a manner akin to
haemoglobins in sickle cell trait.1 Albumin solutions
(4.5% w ⁄ v) have been used clinically as volume
replacement, and as plasma expanders in a more
concentrated form (20% w ⁄ v) for many years. The
high concentration of albumin in plasma, and its strong
net negative charge, means that it is responsible for
around 70% of plasma oncotic pressure and therefore
plays a pivotal role in modulating the distribution of
fluid between compartments. However, albumin has
Correspondence to: Professor T. W. Evans, Royal Brompton Hospital,
Sydney Street, London SW3 6NP, UK.
E-mail: t.evans@rbh.nthames.nhs.uk
6  2002 Blackwell Publishing Ltd
doi: 10.1046/j.1365-2036.2002.00190.
for its therapeutic effects. Among the non-oncotic
properties are its capacity of molecule transportation
and free radical scavenging, its ability to modulate
capillar permeability, neutrophil adhesion and activa-
tion and its haemostatic effects. The following article
reviews these biological effects as well as its structure,
synthesis, catabolism and distribution.
many other biologically important properties which
may be relevant to its actions under physiological
circumstances and in disease.
Albumin is synthesized in polysomes bound to the
endoplasmic reticulum of hepatocytes at a rate of
between 9 and 12 g per day in healthy adults. Albumin is
not stored hepatically and there is therefore no reserve
for release on demand.2 However, under physiological
circumstances only 20–30% of hepatocytes produce
albumin and synthesis can therefore be increased on
demand by a factor of 200–300%. Changes in the rate of
production are governed primarily by alterations in
colloid osmotic pressure, and the osmolality of the
extravascular hepatic space. However, hormonal chan-
ges, for example raised concentrations of insulin,
thyroxine and cortisol, can influence albumin synthe-
sis.3 Surprisingly, growth hormone has no such effect.
Albumin production can be rate limited by amino acid
deficiencies, particularly of leucine, arginine and isoleu-
cine and valine, but these are rarely seen clinically,
except in states of extreme malnutrition. Whether or not
synthesis can be enhanced by amino acid supplementa-
tion in the absence of deficiency is unclear.
Catabolism probably occurs in, or immediately adj-
acent to, the vascular endothelium of tissues, again at a

rate of 9–12 g per day. Albumin is pinocytosed into cells
at a rate which is related to atrial natriuretic peptide
(ANP) concentrations, but is not excessively catabolized
in starvation and deficiency states, possibly because it
represents a poor source of essential amino acids, being
very low in tyrosine residues.
Albumin is predominantly an extravascular protein
and its serum concentration is around 40 g ⁄ L, sug-
gesting a total intravascular mass of about 120 g. The
interstitial concentration is lower (14 g ⁄ L) and varies
in different anatomical regions. However, the total
extravascular mass is around 160 g. Some of this
albumin can easily be mobilized from loose interstitial
tissues, whilst some is tightly bound (particularly in the
skin). There appears to be a circulation of albumin from
the intravascular to extravascular space, returning via
the lymphatic vessels. Such movement has been
measured and represents a circulation half-life of
around 16–18 h.
Some 4–5% of intravascular albumin leaves the intra-
vascular compartment per hour in healthy individuals,
a figure termed the transcapillary escape rate, TER. The
transcapillary escape rate is determined by the capillary
and interstitial free albumin concentrations, microvas-
cular permeability to albumin, the movement of sol-
vents and solutes, and transcapillary electrical charge.
Clearance of albumin and other proteins from the
interstitium is dependent upon lymphatic flow which is
itself determined by interstitial fluid pressure, intrinsic
pumping by the lymphatic vessels, and the effects of
muscular contraction or external compression (e.g.
arterial pulsation).
NON-ONCOTIC PROPERTIES OF ALBUMIN
Transport
Albumin has a strong negative charge, but binds
weakly and reversibly to both cations and anions. It
therefore functions as a circulating depot and transports
molecules for a large number of metabolites including
fatty acids, ions, thyroxine, bilirubin and amino acids
(Table 1). Albumin also binds covalently and irrevers-
ibly with d-glucose and d-galactose. The glycosylation of
albumin, which is to a certain extent age-dependent,
has effects upon its charge and therefore may influence
capillary permeability characteristics. Glycosylated
albumin is thought to have a major role in the
pathogenesis of atherosclerotic disease in diabetics.
 2002 Blackwell Publishing Ltd, Aliment Pharmacol Ther 16 (Suppl. 5), 6–11
13652036, 2002, s5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2036.16.s5.2.x by Cochrane Mexico, Wiley Online Library on [28/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
REVIEW: ALBUMIN AS A DRUG 7
Table 1. Albumin is a transport vehicle for a variety of substances
and binds a number of drugs
Albumin is a transport vehicle for:
s Cholesterol
s Bile pigments
s Nitric oxide
s Fatty acids
s Metals
Albumin interacts with:
s Phenytoin
s NSAIDs
s Digoxin
s Midazolam
s Thiopental
s Antibiotics
Free radical scavenging
Albumin is the major extracellular source of the
reduced sulphydryl groups which are present on a
single exposed cysteine residue at position 31 in the
molecule. These sulphydryl groups, termed thiols, are
avid scavengers of reactive oxygen and nitrogen species,
especially the superoxide hydroxyl and peroxynitrite
radicals. Albumin can also limit the production of these
reactive species by binding free copper Cu2+, an ion
known to be particularly important in accelerating the
production of free radicals. In sepsis, the administration
of human albumin (200 mL, 20% w ⁄ v) has been
demonstrated to lead to significantly increased levels
of plasma albumin, which remained significantly
increased 4 h following administration.4 Total plasma
thiol levels at the same time showed similar trends.
Unlike the albumin measurements, however, where a
significant fall between 5 min and 4 h following
administration occurred, thiol remained significantly
elevated for up to 18 h following albumin administra-
tion. These results have several possible implications.
First, they strongly suggest that an increase in plasma
protein thiols associated with albumin administration is
sustained long-term compared with plasma albumin
levels, which is indicative of an albumin-mediated thiol
exchange in the plasma of these patients. Second, given
that albumin accounts for most of the total plasma thiol
content in normal healthy individuals (the remainder
being associated particularly with gamma globulins,
plasmin and fibrinogen), albumin may in this way
influence redox balance (Figure 1), which has a number
of important implications for other indices of critical
illness, including capillary permeability, rheological
 13652036, 2002, s5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2036.16.s5.2.x by Cochrane Mexico, Wiley Online Library on [28/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 T. W. EVANS

Pro-oxidant Anti-oxidant Capillary permeability

Under physiological circumstances there is a net
Transition metals Transferrin
Haem/haemoglobin Ceruloplasmin
movement of albumin from the intravascular to the
XOD/hypoxanthine Albumin interstitial space and back, via the lymphatic vessels
Hydrogen peroxide Ferritin
(transcapillary escape rate, see above).5 Albumin may
Superoxide HO-1
Hydroxy radicals Bilirubin
itself directly influence vascular integrity, by binding in
Peroxynitrite Glutathione the interstitial matrix and sub-endothelium and by
Hypochlorous acid Vitamin C & E altering permeability of these layers to large molecules
Organic radicals NO
SOD
and solutes.6, 7 Indirect effects may be mediated firstly
catalase by the binding of arachidonic acid (AA), which itself
increases capillary permeability.8 Second, polynitroxyl-
Figure 1. Redox balance. The redox state of an environment is
ated albumin (PNA) protects tissues against ischaemic
determined by the extent to which molecules within it are oxidized
or reduced. Pro-oxidant and anti-oxidant forces are shown. reperfusion injury, possibly by enhancing tissue redox
activity. Certainly, polynitroxylated albumin has been
changes, cell signalling processes, antihaemostatic shown to be a potent inhibitor of xanthine–xanthine
effects and drug metabolism and transport. oxidase mediated adhesion of human neutrophils to
cultured human endothelial cells.9 The beneficial effects
of polynitroxylated albumin may therefore be attributed
Inflammatory ⁄ anti-inflammatory effects
to the attenuation of leucocyte–endothelial cell interac-
The optimal fluid for resuscitation in patients with tion. The influence of other colloids on changes in
critical illness has yet to be designed, but in addition to microvascular integrity are less well characterized.
providing optimal intravascular filling, it would ideally However, increased vascular permeability induced by
favourably modulate the inflammatory processes that endotoxemia can be attenuated by hypertonic saline,
characterize sepsis, the systemic inflammatory response with or without dextran.10 Hypertonic saline–dextran
syndrome (SIRS) and their vascular sequelae. Patients also improves intestinal perfusion and survival in
with these syndromes develop increased vascular porcine septic shock.11 In experimental models of
permeability, leading to tissue oedema formation, ischaemic reperfusion, hydroethylstarch solutions
dysfunctional vasomotor function with disordered de- reduce capillary permeability and tissue oedema forma-
livery of cellular nutrients, and rheological changes tion compared to crystalloids, and decrease both
characterized by increased neutrophil rolling, adherence pulmonary and splanchnic injury and xanthine oxidase
and activation (Figure 2). release after hepatoenteric ischaemic reperfusion.12

Figure 2. Mechanism of the systemic

inflammatory response syndrome and of
the beneficial effects of albumin.

 2002 Blackwell Publishing Ltd, Aliment Pharmacol Ther 16 (Suppl. 5), 6–11

Moreover, the increased permeability of the mesenteric
capillary bed in rodent endotoxaemia is attenuated
equally by resuscitation using either albumin or cry-
stalloid,13 suggesting that changes in endothelial integ-
rity may be favourably influenced by volume repletion,
independent of changes in oncotic pressure.
Rheological changes, neutrophil adhesion and activation
Hydroethylstarch solutions decrease endothelial cell
activation in vitro compared to albumin.14 Such effects
may be due to a free radical scavenging capacity or
to a beneficial effect on cytokine release.15 Moreover, a
moderate increase in the expression of complement
receptors on the surface of polymorphonuclear leuco-
cytes has been described following the incubation of
whole blood with colloids. Neutrophil oxidative burst
activity is also markedly increased following incubation
with artificial colloids and crystalloids, although little
such activation was seen using albumin.16 Indeed,
human serum albumin has been shown to suppress the
respiratory burst of neutrophils in response to exposure
to cytokines relevant to the pathogenesis of critical illness
(tumour necrosis factor—TNF) and complement compo-
nents (e.g. C5A). Moreover, human serum albumin
selectively and reversibly inhibits tumour necrosis factor-
induced neutrophil spreading and the associated fall in
cAMP.17 By contrast, albumin, gelatin or hydroethyl-
starch in moderate amounts show no short-term effects
on adhesion or granulocyte activation in patients
undergoing anaesthesia for orthopaedic surgery.18
Cell signalling processes
Albumin in the reduced state contains a single exposed
thiol group,19 which is the principal extracellular
antioxidant and chiefly responsible for maintaining
Figure 3. Free thiols, of which albumin is
the biggest intravascular source, have been
shown to be important factors in deter-
mining the DNA binding activity of active
transcription factors including NF-jB,
thereby potentially influencing processes
which determine cellular fate ⁄ apoptosis.
 2002 Blackwell Publishing Ltd, Aliment Pharmacol Ther 16 (Suppl. 5), 6–11
13652036, 2002, s5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1046/j.1365-2036.16.s5.2.x by Cochrane Mexico, Wiley Online Library on [28/05/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
REVIEW: ALBUMIN AS A DRUG 9
the redox state of plasma. Redox regulation at a
transcriptional level of the ubiquitous cell signalling
moiety nuclear factor kappa B (NF-jB) has been
described. Moreover, free thiols have been shown to be
important factors in determining the DNA binding
activity of active transcription factors including
NF-jB,20 thereby potentially influencing processes
determining cellular fate or apoptosis (Figure 3). Albumin
administered to critically ill patients increases plasma
thiol levels, even after it is cleared from the circulation,
presumably by virtue of exchange mechanisms with
as-yet unidentified plasma constituents.21 This may
initiate cascades of thiol oxidative–reductive reactions
that ultimately influence cellular signalling processes.
Coagulation ⁄ haemostatic effects
Albumin has an antithrombotic, anticoagulant effect,
possibly because of its capacity to bind nitric oxide (NO)
to form S-nitrosothiols,22 thereby inhibiting the rapid
inactivation of NO and allowing prolongation of its anti-
aggregatory effects on platelets. Thus, priming of the
cardiopulmonary bypass circuits with albumin solutions
may reduce platelet deposition to 4–5% of that observed
for an equivalent pre-treatment with normal saline.
Other studies have shown that this practice has no
clinically detectable advantage in terms of haemostasis,
chest tube drainage or requirement for blood transfu-
sion.22, 23 In the USA, bleeding complications have been
reported following the administration of hydroethyl-
starch 480 ⁄ 0.7, although when given in doses below
1.5 L these are no greater than expected with other
colloid solutions.24 However, hydroethylstarch with a
high initial molecular weight or with a high in vivo
molecular weight seems to have more unfavourable
effects on coagulation than medium or lower molecular
weight hydroethylstarch that is easier to degrade,25

10 T. W. EVANS
although the duration of effect is less, through its faster
elimination. Finally, using thromboelastography, in vitro
studies have suggested that whereas gelatin solutions
were less intrinsically anticoagulant than hydroethyl-
starch, 10% dextran 40 had the strongest effect.26
Pharmacological interactions, drug binding
There are four discrete binding sites on the albumin
molecule, which each have varying specificity for
different substances.27 Ligands can compete at a single
site, or may compete by altering the affinity of remote
sites by conformational changes to the tertiary structure
of the molecule. Thus, drugs binding at the same site
compete for occupancy and are likely to displace one
another (e.g. warfarin, phenytoin), whilst others drugs
known to be highly albumin-bound in plasma but
binding at separate sites may not displace each other
(e.g. warfarin, diazepam). Drugs with which albumin
interacts in a highly clinically significant fashion owing
to their highly protein-bound state and low margins of
safety include warfarin, phenytoin, non-steroidal anti-
inflammatory drugs and digoxin. Midazolam, thiopental
and a number of antibiotics also interact with albumin
in this fashion. The volume of distribution of drugs
bound to albumin may increase in hypoalbuminaemic
states, thereby reducing their efficacy. The adminis-
tration of mixtures of loop diuretics (e.g. frusemide
(furosemide)) with albumin has therefore been advoca-
ted, although this has been shown to be ineffective in
cirrhotic patients with ascites.28
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REVIEW: ALBUMIN AS A DRUG 11
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