Significance of Protein/Tissue Binding of Drugs

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Chapter: Biopharmaceutics and Pharmacokinetics : Protein Binding of Drugs

Significance of Protein/Tissue Binding of Drugs : Absorption, Systemic Solubility of Drugs, Distribution, Tissue Binding, Apparent Volume of Distribution and Drug Storage, Elimination, Displacement Interactions and Toxicity, Diagnosis, Therapy and Drug Targeting




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 stop. However, binding of the absorbed drug to plasma proteins decreases free drug concentration and disturbs such equilibrium. Thus, sink conditions and the concentration gradient are re-established which now act as the driving force for further absorption. This is particularly useful in case of ionised drugs which are transported with difficulty.


Systemic Solubility of Drugs

Water insoluble drugs, neutral endogenous macromolecules 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.


Plasma protein binding restricts 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 function (maintains equilibrium between the free and the bound drug). A protein bound drug in particular does not cross the BBB, the placental barrier and the glomerulus.

Tissue Binding, Apparent Volume of Distribution and Drug Storage

A drug that is extensively bound to blood components remains confined to blood. Such a drug has a small volume of distribution. A drug that shows extravascular tissue binding has a large volume of distribution. A tissue or blood component that has great affinity for a particular drug acts as a depot or storage site for that drug; for example, RBC is a storage site for the lipophilic compound tetrahydrocannabinol.

The relationship between tissue-drug binding and apparent volume of distribution can be established as follows –

Vd = Amount of drug in the body / Plasma drug concentration = X/C              (4.1)

or, the amount of drug in the body, X = Vd C                 (4.2)

Similarly, we can write,

Amount of drug in plasma = Vp C                   (4.3)

and, Amount of drug in extravascular tissues Vt Ct                     (4.4)

The total amount of drug in the body is the sum of amount of drug in plasma and the amount of drug in extravascular tissues. Thus,

Vd C = Vp C + Vt + Ct                         (4.5)

Where, Vd = apparent volume of distribution of drug

Vp = volume of plasma

Vt = volume of extravascular tissues

Ct = tissue drug concentration

Dividing equation 4.5 with C we get:

Vd = Vp + Vt                 (4.6)

The fraction of drug unbound (fu) in plasma is given as:

fu = Concentration of unbound drug in plasma / Total plasma drug concentration = Cu / C        (4.7)

Similarly, fraction of drug unbound to tissues is:

fut = Cut / Ct                    (4.8)

Assuming that at distribution equilibrium, the unbound or free drug concentration in plasma equals that in extravascular tissues i.e. Cu = Cut, equations 4.7 and 4.8 can be combined to give:

Ct / C = fu / fut                        (4.9)

Substitution of equation 4.9 in 4.6 yields:

Vd = Vp + [Vt fu]/fut                   (4.10)

From equation 4.10 it is clear that greater the unbound or free concentration of drug in plasma, larger its Vd.


Only the unbound or free drug is capable of being eliminated. This is because the drug-protein complex cannot penetrate into the metabolising organ (liver). 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; for example, tetracycline, which is only 65% bound, has an elimination half-life of 8.5 hours in comparison to 15.1 hours of doxycycline which is 93% bound to plasma proteins. However, penicillins have short elimination half-lives despite being extensively bound to plasma proteins. This is because rapid equilibration occurs between the free and the bound drug and the free drug is equally rapidly excreted by active secretion in renal tubules.

Displacement Interactions and Toxicity

As stated earlier, displacement interactions are significant in case of drugs which are more than 95% bound. This is explained from the example given in Table 4.4. A displacement of just 1% of a 99% bound drug results in doubling of the free drug concentration i.e. a 100% rise. For a drug that is bound to a lesser extent e.g. 90%, displacement of 1% results in only a 10% rise in free drug concentration which may be insignificant clinically.

TABLE 4.4.

Influence of Percent Binding and Displacement on Change in Free Concentration of Drugs

Kernicterus in infants is an example of a disorder caused by displacement of bilirubin from albumin binding sites by the NSAIDs ans sulphonamides. Another example discussed earlier was that of interaction between warfarin and phenylbutazone. Yet another example of displacement is that of digoxin with quinidine. Digoxin represents a drug with a large volume of distribution (i.e. shows extensive extravascular tissue binding). Since displacement interactions may precipitate toxicity of displaced drug, a reduction in its dose may be called for. This may become necessary for a drug having a small Vd such as warfarin since displacement can result in a large increase in free drug concentration in plasma. With a drug of large Vd such as digoxin, even a substantial increase in the degree of displacement of drug in plasma may not effect a large increase in free drug concentration and dose adjustment may not be required. This is for two reasons—one, only a small fraction of such a drug is present in plasma whereas most of it is localized in extravascular tissues, and secondly, following displacement, the free drug, because of its large Vd, redistributes in a large pool of extravascular tissues. The extent to which the free plasma drug concentration of drugs with different Vd values will change when displaced, can be computed from Equation 4.10.


The chlorine atom of chloroquine when replaced with radiolabelled I-131 can be used to visualize melanomas of the eye since chloroquine has a tendency to interact with the melanin of eyes. The thyroid gland has great affinity for iodine containing compounds; hence any disorder of the same can be detected by tagging such a compound with a radioisotope of iodine.


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 tool. HDL is similarly transported more to adrenal and testes. An example of site-specific drug delivery in cancer treatment is that of oestramustine. Oestradiol binds selectively and strongly to prostrate and thus prostrate cancer can be treated by attaching nitrogen mustard to oestradiol for targeting of prostrate glands. Drug targeting prevents normal cells from getting destroyed.

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