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PROTEIN BINDING OF DRUGS
INTRODUCTION TO PROTEIN BINDING:
A drug in the body can interact with several tissue components of which the two
major components are:
1. Blood, and
2. Extravascular tissues.
The interacting molecules are generally the macromolecules such as proteins, DNA, or adipose. The
proteins are particularly responsible for such an interaction. The phenomenon of complex formation
with proteins is called as protein binding of drugs. Protein binding may be divided into:
1.Intracellular binding:
Where the drug is bound to a cell protein which may be the drug receptor; if so, binding elicits a
pharmacological response. These receptors with which drug interact to show response are called as
primary receptors.
2.Extracellular binding:
Where the drug binds to an extracellular protein but the binding does not usually elicit a
pharmacological response. These receptors are called secondary or silent receptors.
The bound drug is pharmacologically inert i.e. an extra cellular protein bound drug is neither
metabolized nor excreted nor it is active pharmacologically. A bound drug is also restricted since it
remained confined to a particular tissue for which it has greater affinity. Moreover, such a bound drug,
because of its enormous size, cannot undergo membrane transport thus, its half-life is increased.
MECHANISM OF PROTEIN-DRUG BINDING:
Binding of drugs to proteins is generally reversible and involves:
1. Hydrogen bonds
2. Hydrophobic bonds
3. Ionic bonds, or
4. Vandervaalsforces1.
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DRUG PROTEINS IN PLASMA:
The major drug binding proteins in plasma are:
Albumin
1-acid glycoprotein
Lipoproteins.
Albumin and 1-acid glycoprotein have structurally selective binding sites for
drugs, in the same way that the active sites for the enzymes are structurally selective for substrates. Each
albumin molecule has at least 6 distinct binding sites for drugs and endogenous compounds. Two of
these very tightly and specifically bind long chain fatty acids. There is another site which selectively
binds bilirubin. There are two major drug binding sites called site I and site II which mainly bind acidic
drugs. Site I binds drugs such as warfarin and phenylbutazone, whereas site II binds drugs such as
diazepam and ibuprofen. Drugs which bind at the same site can be predicted to displace each other
competitively when administered together. Alpha l-acid glycoprotein is an acute phase reactant which
has one binding site selective for basic drugs such as disopyramide and lignocaine. Binding of drugs to
lipoproteins and red cell and other membranes is more a dissolving of the drugs in the lipids of the
membrane rather than a true binding reaction. Very lipid soluble drugs partition preferentially into the
membrane lipids rather than the plasma water. Some drugs bind strongly to particular tissue components
such as DNA (e.g. some anticancer drugs and quinacrine) and melanin-rich tissues (e.g. chloroquine,amiodarone).
The binding of a drug to a protein binding site is a saturable process governed by the same mass action
expression that describes the interaction of a substrate with an enzyme binding site. The extent to which
a drug is bound in plasma or blood is usually expressed as the fraction unbound fraction unbound =
unbound drug concentration. The tighter the binding,. the lower is the fraction unbound. The distinction
between fraction unbound and unbound concentration is important as we shall see below. The
fractionunbound of a drug is determined by:
The affinity of the drug for the protein
The concentration of the binding protein
The concentration of drug relative to that of the binding protein2.
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In most cases, drug concentrations at therapeutic doses are well below those of the binding protein and
the fraction unbound is constant across the therapeutic range of drug concentration. However, the
concentration of al-acid glycoprotein is relatively low, and saturation of the binding sites can occur in
the therapeutic range. An example is disopyramide where the unbound concentration increases linearly
with dose, but there is a less than proportionate increase in total concentration as saturation occurs
causing fraction unbound to increase. Albumin concentrations are high, and saturation rarely occurs with
drugs binding to this protein. An exception is salicylate which has high therapeutic concentrations.
The knowledge of binding properties of drugs is of considerable importance not so much because of
possible displacement interactions with other drugs, but because it is assumed that only a small fraction
of the circulating drug (the free drug concentration) is able to cross membranes, especially the blood
brain barrier and the endothelial barrier in the heart. Propofol has a number of effects on the
cardiovascular system including impairment of myocardial contractile force and a protective effect
against ischaemia-reperfusion syndrome, but these effects often occur in vitroat concentrations which
are very different from those seen in patients. Thus, precise knowledge of the concentration of drug able
to reach the target sites may help in differentiating between the numerous effects described and those
which might be observed at therapeutic concentrations. Another application lies in the fact that
pharmacokinetically driven infusion of anaesthetic agents is of growing interest. The basic concept of
computer driven anaesthesia is to link dosing to pharmacokinetics and to pharmacodynamics. In that
context, the precision of prediction models will certainly be improved if we can take into account the
free fraction (and the factors leading to changes in this fraction). We, therefore, studied the binding of
propofol on red blood cells, human serum and human serum fractions.
The serum obtained from the volunteers was pooled and frozen for no more than 4 weeks before use.
The following fractions were purchased from Sigma Chemical. Human serum albumin (HSA) prepared
from Cohn fraction V (globulin free) ,human 1-acid glycoprotein (AAG) prepared from Cohn fraction
VI ,human high density lipoproteins (HDL) and human low density lipoproteins (LDL). The same buffer
with the following composition was used throughout the study: NaCl; KCl; NaH2PO4Na2HPO4CaCl2,;
MgCl2. Albumin was dissolved in buffer at two concentrations (300 m and 60 m, i.e. respectively 20
and 4 g l1
). AAG was dissolved in buffer at a concentration of 20 m(0.9 g l1
), LDL was dissolved at
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a concentration of 1.4 m (0.2 g l1
apoprotein) and HDL at a concentration of 5.4 m (0.8 g
l1
apoprotein). Human serum and buffer solutions were adjusted to pH 7.40 before use if needed2.
BINDING OF DRUGS
To Blood components:
1. Plasma Proteins
2. Blood cells
To Extra vascular Tissues:
1. Proteins
2. Fats
3. Bones etc.
I. Plasma- protein drug binding:
Blood components mainly plasma proteins and RBCs are the major portion of the bulk that actually
interacts with the drug moieties as soon as they enter the blood systemic circulation. The plasma
proteins being in surplus amounts in the blood undergoes major complexation with drug also this
reaction or process is usually reversible due to large variety available in types of proteins. The sequence
of drug-protein binding is3:
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(a) Binding of drugs to human serum albumins.
The human serum albumin also abbreviated as HSA is a plasma protein with a molecular weight of
650000 and comprises of 59% of total plasma protein content present in the blood. It is most abundantly
present in plasma with a very high potential of binding drugs. It has been widely observed that there is
no equilibrium between the concentration of drug and that of HSA, as the administered dose is usually
smaller as compared to that of plasma proteins present. Almost all types of drugs whether acidic, basic
or neutral drugs undergo significant HSA binding.
Experimental studies have postulated that any drug can bind to numerous protein binding site .In such
circumstances the primary site is the major binding site and the other as the secondary site; for example,
for dicoumarol site I is the primary site while site II is secondary. Those drugs having affinity for the
same binding sites compete with one another. But the non-competitively binding drugs either promote or
inhibit binding of a drug to another site. This is usually accomplished by mechanism of coupling. There
are four different sites for the drugs to bind. Many substances (generally endogenous compounds) such
as tryptophan, saturated fatty acids, unsaturated fatty acids, bile salts or bilirubin etc all exhibit effective
albumin binding . This is due to diversity in the structures of proteins, the structures of free drug moiety
and their affinity towards the protein molecule6.
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The different sites are:
Site I: To this specific site a large population of drugs bind like Non-Steroidal Anti-Inflammatory Drugs
mainly phenylbutazone, indomethacin, many sulfonamides e.g.; sulfamethoxine, sulfamethizole, and
even many anti-epileptic drugs like phenytoin etc. this site is also called as Warfarin binding site or as
Azapropazone binding site.
Site II: This is actually said to be Diazepam binding site. Benzodiazepines, medium chain fatty acids,
ibuprofen, ketoprofen, etc. bind extensively at the very site. This is so because due to structural changes
the following drugs have high and specific affinity for the site. At both the sites I&II many drugs are
known to bind.
Site III: This very protein site is called as Digitoxin binding site
Site IV:This is referred as Tamoxifen binding site.
At the sites III & IV very few drugs are known to bind2.
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(b) Drugs Binding to 1-Acid Glycoprotein i.e.; 1AGP or AAG.
The acid glycoprotein exists with a 44,000 molecular weight and comprises of 0.04 to 0.1 g% of the
total plasma concentration of proteins. It is actually called as the Oromucoid as it mainly binds to basic
drugs like Imipramine, Desipramine, lidocaine, Quinidine, etc.
(c) Binding of drugs to lipoproteins:
Lipoproteins are those macromolecules present in plasma which portends a greater capacity of forming
hydrophobic bonds. The major reason attributed to this is the larger lipid content present in them. But
the plasma concentration of lipoproteins is very limited as compared to that of HSA and AAG. The lipid
core of Lipoproteins has their outer core to be made of Apo proteins while the internal core is a
potpourri containing triglycerides and esters of cholesterol. Lipophilic drugs exhibit greater affinity for
such type of protein binding. Lipoprotein binding is predominant when larger quantity of drugs bind to
them and also in circumstances revealing lower plasma levels of HSA and AAG. The process of
binding involves the dissolution of drug molecules into the lipid core of the protein and hence the
binding capacity is in direct relation with the lipid content. This binding of drugs to lipoproteins is non-
competitive in nature. The lipoproteins have molecular weights ranging from 2 to 3 lakhs. They areclassified on the basis of their density. The 4 classes of lipoproteins are observed depending upon their
variations in density:
1. Very Low Density Lipoproteins (VLDL)2. Low Density Lipoproteins (LDL)3. High Density Lipoproteins (HDL).4. Chylomicrons.3
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(d) Binding of drugs to Globulins:
Different types of plasma proteins are labeled here below:
(i) 1-globulins: This is called as CBG elaborated as corticosteroid binding globulin as itlargely binds to steroidal drugs such as cortisone, hydrocortisone, prednisone etc. Thyroxinand Cyanocobalamin are also effectively bound to above proteins.
(ii) 2-globulins: It binds vitamins A, D,E and K and cupric ions and hence isBroadly called as Ceruloplasmin.
(iii) 1-globulins: As it mainly binds to ferrous ions or ferric compounds areKnown as Transferring binding site.
(iv) 2-globulins: Carotenoids binding is mainly observed.(v) -globulins: Specific antigens binding is observed due to high selectivity and
Specificity of the site4.
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II. Binding of drugs to blood cells:
RBCs are the major blood cells which rates about 40% of total blood. The red blood corpuscles
constitute 95% of the total blood cells concentration in the body. The diameter or the width of the
RBCs is 500 times higher than that of plasma proteins. The 3 compartments which being the major
portion of red blood cells to which drugs can bind are:
(a)Hemoglobin: this has molecular weight & structural similarity to that of HAS but theconcentration is much higher than of albumins in blood. Examples of drugs that bind are
phenytoin, pentobarbital etc.
(b)Carbonic Anhydrase: Carbonic anhydrase inhibitors mainly bind to the site like chlorthaizine.(c)Red Blood cell membrane: basic drugs like imipramine are known to bind to RBC membrane.
Both the hydrophilic and lipophilic drugs can enter RBCs but the lipophilic drugs can do to a
greater extend7.
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(d)TISSUE LOCALIZATION:The tissue binding of drugs are also very significant processes occurring in the body. Unlike
HSA, the body tissues constitute100 times that of HAS i.e.; about 40% of the total body weight.
Multiple tissue drug binding are feasible. Tissue drug binding is very essential and vital process
as it assists in enhancing the apparent volume of distribution for drugs as this follows a direct
relation with the ratio of concentration of drug in body to-free or unbound drug in plasma. Also it
results in prolonged duration of action due to increase in half-life reason being the localization of
drug at a specific site in the tissues. Studies also reveal that a very large population of drugs no
matter acidic, basic or neutral undergoes reversible binding whereas the plasma protein drug
binding exhibits vice-versa. The order of binding to extravascular tissues is given as:
1. Liver> Kidney> Lung> Muscle. Lets have an overview of some tissue drug binding. Liver:Irreversible binding of drugs like paracetamol and their epoxide-metabolites to liver tissues
results in hepatotoxicity.
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2. Lungs: like imipramine, chlorpromazine and antihistamines accumulation of drugs likeimipramine, desipramine or other drugs in lungs eventually leads to congestion in heart or may
even produce severe lungs cancer.
3. Kidneys: the protein called as metallothion is widely present in kidneys which have a tendencyto undergo complexation with heavy metals such as lead, mercury and cadmium. This gradually
paves path for the major renal failures or renal toxicity.
4. Skin: Many drugs are known to accumulate in skin with subsequent reaction with melanin whichcan ultimately result in skin diseases. Drugs such as chloroquine, phenothiazines are usually
involved in this.
5. Eyes: the retinal pigments of the eye also contain melanin. Drugs like chlorquine are responsiblefor retinopathy as these drugs they interact with the melanin present in the retinal pigments.
6. Bones: bones are made up of calcium and most of the antibiotics mainly like tetracycline exhibitsextensive binding to bones and teeth. The permanent brown-yellow discoloration of teeth is an
adverse effect of administration of such antibiotics to newly born babies or infants. Similarly
lead also generates similar responses with teeth and bones6.
Factors affecting Protein Drug Binding.
DRUG RELATED FACTORS:
(a) Physiochemical characteristics of the drug.
Lipophilicity is the most desirable physiochemical parameter that is perquisite for protein binding to
occur. Also an increase in the lipid content of drug moiety eventually enhances the rate as well as
extends of protein binding process. As observed in case of intramuscular. Injection of cloxacillin as
attributed to greater lipophilicity displays 95% protein binding.
(b) Concentration of drug in the body.
Alteration in the concentration of drug substance as well as the protein molecules or surfaces
subsequently brings alteration in the protein binding process.
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(c) Drugs affinity towards protein/tissue.
This factor entirely depends upon the degree of attraction or affinity the protein molecule or tissues have
towards drug moieties. For Digoxin has more affinity for cardiac muscles proteins as compared to that
of proteins of skeletal muscles or those in the plasma like HSA.
PROTEIN/TISSUE RELATED FACTORS:
(a) Concentration of protein/binding component:
This is the most important tissue related parameter to be given priority. As the human serum plasma
proteins constitute the major portion of the plasma proteins, a large number of drugs undergo an
extensive binding with them as compared to the concentration of other protein molecule(b) Number of binding sites on the protein
In association to the concentration of proteins molecules available the number of binding sites available
in the protein molecules is also significant. Albumin not only possesses large number of binding sites
but also has greater potential of carrying out binding process. Numerous drug exhibit multiple site
binding with albumin molecules in plasma like fluocloxacillin, ketoprofen, indomethacin etc.
(c) Physicochemical properties of protein/binding component:
Lipoproteins and adipose tissue tend to bind lipophilic drugs by dissolving them in their lipid core. Thephysiological pH determines the presence of active anionic and cationic groups on the albumin
molecules to bind a variety of drug3.
DRUG INTERACTIONS
(a) Competitive binding of drugs
Displacement interactions are predominant ones among these reactions. In case where two or more
drugs have same or identical affinity for a same site then they struggle with one another to bind at thesame site. Consider a drug I is bound to a specific site on the molecule and if a second drug called as
Drug II is administered now, then the drug meaty having greater affinity towards the bound site would
effectively displace the former drug. This phenomenon is said to be Displacement reaction. The drug
which is been removed from its binding site is said to be displaced drug while the one that does the
displacement is called as displacer.
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The best example for such interactions is the competitive protein binding that occurs between Warfarin
and phenylbutazone for HSA, as both are potent binders of HAS, where phenylbutazone is displacer
while warfarin is displaced. Clinically such reaction acquire importance when the displaced drug (any)
is more than 95% bound to plasma proteins, or occupies small volume of distribution even less than that
of 0.15 L/Kg. also when the active drug or the administered pharmacological agent possess narrow
therapeutic index. Such situation may also develop in case the displacer drug has greater affinity or at
the same time the drug/protein concentration ratio is very high and exhibits a very rapid and significant
increase in the plasma concentration of drug.
(b) Competition between drugs and normal body constituents:
Among the various normal body constituents, the free fatty acids are known to interact with a number of
drugs that bind primarily to human serum albumin. Bilirubin binding to human serum albumin can be
impaired by certain drugs and is of great concern in neonates whose BBB and bilirubin metabolizing
capacity are not very efficient. Acidic drugs displace bilirubin from its albumin-binding site. The free
bilirubin is not conjugated by the liver of the neonates and crosses the BBB and precipitates the
condition called as kernicterus5.
(c)Allosteric changes in protein molecule:
This process involves alteration of the protein structure by the drug or its metabolite thereby modifying
its binding capacity. The agent that produces such an effect is called as allosteric effector,e.g. aspirin
acetylates the lysine fraction of albumin thereby modifying its capacity to bind NSAIDs like
phenylbutazone(increased affinity) and flufenamic acid (decreased affinity).
PATIENT RELATED FACTORS:
Patients related factors have their own importance after all the drug has to generate its response on to the
administered patient. In this numerous parameters are taken into account like Age, diseased state,
pharmacokinetic and Pharmacodynamic characteristics. Protein content and its specific type greatly
varies with the age factor.
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Neonates and young infants:
The neonates or newly born babies have very low levels of albumins in the plasma thereby resulting in
rebound concentration of drug that is primarily bind to albumin is a major shortcoming. As far as elderly
patients are concerned the albumin levels goes down while the concentration of AAG is high enough.
Intersubject variations:
Intersubject variability in drug binding as studied with few drugs showed that the difference is small and
no more than two fold. These differences have been attributed to genetic and environmental factors.
Disease states:
The alterations in protein content and thereby the rate and extend of protein binding is greatly influenced
by the albumin which is the major drug binding protein. This may ultimately lead to hypoalbuminemia
which eventually with the pace of time completely impairs the entire protein drug binding process. For
such situations the basic pathological conditions of diseases like trauma, burns, renal, cardiac or hepatic
failure etc.. are largely responsible. Pharmacokinetics as well as Pharmacodynamic of drugs greatly
influences the distribution, clearance and thus the biotransformation of drugs to a greater extend.
Usually an increased potential of toxicity is observed due to increased concentration of free or the
unbound drug.
Putting in a nut shell, all factors, drug interactions and patient related factors that affect protein binding
o tissue binding of drugs influence:
(1)Pharmacokinetics of drugs.
(2)Pharmacodynamics of drugs.
SIGNIFICANCE OF PROTEIN BINDING OF DRUGS:
Targeted drug delivery is the major research area in this era of medical and life
sciences. The binding of drugs to lipid containing proteins called as lipoproteins is effectively utilized
for controlled and site-specific drug delivery. For this the hydrophilic drug moieties are of great priority.
The major application of delivering the drug at a predetermined rate is highly beneficial in treatment and
appreciable management of cancer therapies.
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The best requirement of site-specific drug delivery is revealed in cancer treatment with that of
estramustine. Thus binding of suitable anti neoplastic agents like vincristine or vinblastine with the LDL
is desirable to prevent the normal cells from damage caused by the administered drug.
The protein drug binding also portends an advantage of efficient drug distribution, absorption
and finally prolonged duration of action for longer treatment of chronic diseased conditions.
(1)Absorption:
The absorption equilibrium is attained by transfer of free drug from the site of administration into the
systemic circulation and when the concentration in these two compartments become equal. Following
equilibrium, the process may stop6.
(2)Systemic solubility of drugs:
Water insoluble drugs, neutral endogenous macro molecules such as heparin and several steroids and oil
soluble vitamins are circulated and distributed to tissues by binding especially to lipoproteins which act
as a vehicle for such hydrophobic compounds.
(3)Distribution:
Plasma protein binding restrict the entry of drugs that have specific affinity for certain tissues. This
prevents accumulation of a large fraction of drug in such tissues and thus, subsequent toxic reactions.
Plasma protein-drug binding thus favours uniform distribution of drugs throughout the body by its buffer
action1.
(4)Elimination:
Only the unbound or free drug is capable of being eliminated. This is because drug-protein complex
cannot penetrate into the metabolizing organ. The large molecular size of the complex also prevents it
from getting filtered through the glomerulus. Thus, drugs which are more than 95% bound are
eliminated slowly i.e. they have long elimination half-lives.
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(5)Displacement Interactions and toxicity:
Displacement interactions are significant in case of drugs which are more than 95%bound. A
displacement of just 1% of a 99% bound drug results in doubling of the free drug concentration i.e. a
100% rise.
Kernicterus in infants is an example of a disorder caused by displacement of bilirubin from albumin
binding sites by the NSAIDs and sulphonamides.
(6)Diagnosis:
The thyroid gland has great affinity for iodine containing compounds; hence any disorder of the same
can be detected by tagging of such a compound with a radioisotope of iodine.
(7)Therapy and drug targeting:
The binding of drugs to lipoproteins can be used for site-specific delivery of hydrophilic moieties. This
is particularly useful in cancer therapies since certain tumour cells have greater affinity for LDL than
normal tissues. Thus, binding of a suitable antineoplastic to it can be used as a therapeutic tool7.
CONCLUSION:
Drugs widely used in clinical pharmacology, with few exceptions, are hepatically eliminated and
circulate in the blood bound to plasma proteins. Often, the degree of binding is high (>90%). This fact
has led to a widespread belief that such drugs may frequently participate in drug-binding interactions.
The logic is as follows: Co-administration of drugs can result in a highly bound drug displacing a less
avidly bound drug from its binding sites. This leads to greater amounts of free, nonprotein-bound, drug
available for distribution to the sites of action. As free drug is a major determinant of pharmacologic
effects, these drug interactions could result in toxicity and/or enhanced efficacy. This reasoning
simplifies a complex situation where compensatory changes occur in the body to buffer the impact of
drug-binding interactions. There are few examples where the above events have been documented to
occur with drugs leading to substantial clinical consequences. Although protein-binding displacement
interactions are generally of minimal clinical significance, this is an assumption not based on evidence,
but rather the lack of it7.
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REFERENCES:(1)Brahamnkar.D.M, Jaiswal.B.Sunil In Textbook of Biopharmaceutics and
Pharmacokinetics, Edition I, Vallabh Prakshan, Delhi, 110088, 16-51.
(2) Wagner, J.G.: Biopharmaceutics and Relevant Pharmacokinetics, Washington, D.C,Drug I
(3)Sharjel, L.Yu, A.B.C.: Applied Biopharmaceutics and Pharmacokinetics, 2nd edition,Connecticut, Appleton Century Croffts, 1985ntelligence Publications, 1971.
(4) Niazi, S.: Textbook of Biopharmaceutic and Clinical Pharmacokinetics, New York,
Appleton Century Crofts, 1979.
(5) Reindenburg, M.M. and Erill, S.: Drug-Protein Binding, New York, Praeger, 1986.
(6) Mc Elany, J.C.: Buccal Absorption of Drugs. In: Encyclopedia of Pharmaceutical
Technology, vol. 2(Swarbick, J. and Boylan, JC.,eds.), New York, Marcel Dekker, Inc.,
1990.
(7) Mayershon, M.: Principles of Drug Absorption. In.: Modern Pharmaceutics, 2nd edition.
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