Pharmaceutical sciences
Biopharmaceutics & Pharmacokinetics Drug Distribution
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Development Team
Principal Investigator
Dr. Vijaya Khader
Former Dean, Acharya N G Ranga Agricultural University Prof. Farhan J Ahmad JamiaHamdard, New Delhi
Paper Coordinator Dr. Javed Ali
JamiaHamdard, New Delhi
Content Writer Dr. Sanjula Baboota
JamiaHamdard, New Delhi
Content Reviewer Prof. Dr. Ashu Mittal
KIET School of Pharmacy, Ghaziabad
Pharmaceutical sciences
Biopharmaceutics & Pharmacokinetics Drug Distribution
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CONTENTS
Introduction
Steps in drug distribution
Factors affecting distribution of drugs
Characteristics of various proteins affecting drug distribution
Volume of distribution
Summary
DRUG DISTRIBUTION SYSTEM
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INTRODUCTION
After entry of drugs into systemic circulation by different routes including intravascular injection or oral administration or any of the various extravascular sites, the drug enters into a number of processes called disposition processes.The process involved in the disposition is mention below as following-
Distribution- It is defined as the reversible transfer of drug between blood and other remaining compartments of the body.
Elimination- It is defined as the irreversible loss of drug from the body. It is further divided into two mechanisms such as biotransformation (metabolism) and excretion.
STEPS IN DRUG DISTRIBUTION
The process of moving a drug from the bloodstream to tissues is referred to as a distribution, which involves following steps as discussed below and shown in figure 1.
Figure 1: Schematic steps involved in the distribution of drug.
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1. The free and unbound drug present in the blood stream permeates through the wall of the capillary and enters into the interstitial/ extracellular fluid (ECF).
2. The drug present in the ECF permeates through the tissue cells and enters into the intercellular fluid. This is the rate limiting step,which involves two major factors such as:
Rate of perfusion to the extracellular tissue.
Permeability of membrane for drugs.
CHARACTERSTICS OF DISTRIBUTION PROCESS
1. Distribution is a passive process - driving force is concentration gradient between the blood and extravascular tissues until equilibrium is achieved.
2. The distribution of drugs in the body depends on their lipophilicity and protein binding:
Low plasma binding or high tissue binding or high lipophilicity usually means an extensive tissue distribution. In pharmacokinetics, the distribution is described by the parameter V, the apparent volume of distribution. At equilibrium, V will theoretically not be lower than 7 L in a 70-kg person, but it has no upper limit.
3. The extent to which a drug distributes affects the concentration at steady state.
4. Most drugs exhibit a non-uniform distribution in the body with variations that are largely determined by the ability to pass through membranes and their lipid/water solubility.
5. Small water soluble molecules and ions diffuse through aqueous channels or pores Lipid – soluble molecules penetrate the membrane itself. Water-soluble molecules and ions of moderate size (m. w. > 50 or more) cannot enter cells easily except by special transport mechanisms.
Importance of distribution process
Plays an important role in the onset and intensity of a pharmacological response as distribution process makes the drug reach the site of action. Eg: short duration of action of thiopental is due to its fast distribution to body muscles and fats removing the drug from its site of action i.e. CNS. On the other hand, drugs which can be stored in the body tissues may provide prolonged action if the site of action is embedded in these tissues.
FACTORS AFFECTING DISTRIBUTION OF DRUGS
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Distribution of drug is the process, which is not uniform throughout the body because of a number of reasons. The various factors that affect the rate and extent of drug distribution inside the body are:
I. Membrane permeability which depends on i. Physicochemical properties of drugs
ii. Types and characteristics of various physiological barriers II. Blood perfusion rate
III. Binding of drug to different component i. Binding of drugs to blood
ii. Binding of drugs to extravascular components IV. Miscellaneous factors
i. Age ii. Pregnancy iii. Obesity iv. Diseased state
I. Membrane permeability of drugs
Blood flow to the entire body tissue is in uniform manner, but the distribution of drug between tissues varies because of different tissue membrane permeability, physiochemical properties of drug and physiological barriers that limits the distribution of drug into tissues.
i. Physiochemical properties of drug:
The parametersthat effect the distribution of drug are discussed below- Molecular size
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Smaller the molecular size of the drug, more easily it crossesthe capillary membrane to enter into the extracellular interstitial fluids. Different processes are involved in absorption of different molecular size drugs. Those with a large molecular size undergo endocytosis or facilitated diffusion, while those with smaller molecular sizes utilize aqueous diffusion or lipid channels.
The rate of passive diffusion is inversely proportional to the square root of molecular size.
Therefore, smaller molecules diffuse more readily than larger ones. Only small molecules with size below 50Daltons and water soluble in nature can enter into the cell through aqueous filled channels whereas those with larger size are restricted unless a specialized transport system exists for them.
Degree of ionization
Different drugs are either acidic or basic and are present in ionized or unionized form, which is given by their pKa values. In the body, the ratio of the ionized and unionized forms depends on the pH of the medium.Only the un-ionized fraction of a drug is available to cross the cell membrane because of the lipid nature of the membrane. The degree of ionization of a drug in solution depends on the molecular structure of the drug and the pH of the medium. Most drugs are weak acids or weak bases and exist inequilibrium of un-ionized and ionized forms. The variation in the ratio of the two forms with varying pH is given by the HendersonHasselbalch equation. This may be expressed as:
pH =pKa+ log10 (proton acceptor/ proton donor) ………...…(1) Therefore, for an acid XH the relationship is-
pH = pKa+ log10 [X- ]/ [XH] ………...(2) and for a base X, the corresponding equation is-
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pH =pKa+ log10[X]/ [XH+] ………(3)
The pKais constant for each drug and is the pH at which 50% of the drug molecules are ionized.
It can be seen from the above equations that at a pH below their pKa, weak acids will be more un-ionized, and at a pH above their pKathey will be more ionized. The reverse is true for weak bases.
Ionization affects both the rate at which drug cross membranes and the steady-state distribution of drug molecules between compartments of differing pH. Since, the blood and ECF pH normally remain constant (7.4), they do not have much of an influence on drug diffusion unless there is an alterationin condition such as systemic acidosis or alkalosis.
Lipid Solubility
Non-polar substances dissolve freely in lipids and therefore easily diffuse through cell membranes. Greater solubility in the membrane generates a greater transmembrane concentration gradient, even if the aqueous concentration gradient between two compartments separated by the membrane remains the same. The solubility in the membrane can be expressed as a partition coefficient for the substance distributed between the lipid phase (membrane) and the aqueous phase (environment). The mobility of molecules within the lipid varies very little between different drugs and so the partition coefficient is the most important variable affecting the permeability of the cell membrane.
Protein binding
Only free unbound drug is available to cross the cell membrane. In the plasma, both albumins and globulins are available to which the drugs bind.Ingeneral,albuminbindswith neutraloracidicdrugswhileglobulinsbinds withbasicdrugs.Fordrugsthatare highly protein-bound, small changes in the fraction of protein binding produces large changes in the total amount of unbound drug. Pathological conditions such as acute infective or inflammatory processes, or
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reduction in synthesis capacity due to liver impairment, cause a reduction in albumin concentration and markedly affect the proportions of unbound drugs.
ii. Types and Characteristics of different Physiological barriers
A special structure of membrane (barrier) could be the restriction to the permeability or distribution of drugs to some tissues. Some important barriers are discussed below-
The simple capillary endothelial barrier
The capillary barriers that supply blood to the tissue are not a barrier to the moieties like drugs.
Thus, all drugs whether it is ionised or unionised form with a less molecular size (<600 Daltons) diffuse through the capillary endothelium and into the interstitial fluid. The drugs bound to the blood components are not able to cross the barrier because of the higher molecular size of the complex.
The simple cell membrane barrier
Once the drug diffuses from the capillary wall into the extracellular fluid, then the entry of drugs into the cells of those tissue which are surrounded by membrane are governed by the permeability of drugs. One such type of a barrier is the gastro intestinal cells that are surrounded by the lipoidal barriers which limit the drug absorption.
Blood-Brain Barrier
The capillary membrane between the plasma and brain cells is much less permeable to water- soluble drugs than is the membrane between plasma and other tissues. Thus, the transfer of drugs into the brain is regulated by the blood-brain barrier. To gain access to the brain from the capillary circulation, drugs must pass through cells rather than between them. Only drugs that
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have a high lipid-water partition coefficient can penetrate the tightly opposed capillary endothelial cells.
Drugs that are partially ionized and only moderately lipid soluble will penetrate at considerably slower rates. Lipid-insoluble or highly ionized drugs will fail to enter the brain in significant amounts. Because the pH of the cerebrospinal fluid is about 7.35, there is some tendency for weak organic bases to concentrate in the cerebrospinal fluid and for weak organic acids to be excluded. In addition, because only the unbound form of a drug is available for diffusion, extensive plasma protein binding also can have dramatic effects on the extent of drug transfer into the brain.
Blood cerebro-spinal fluid (CSF) barrier
The cerebro-spinal fluid (CSF) is formed by the choroidal plexus of the lateral, third and fourth ventricles. This fluid is similar in composition to the ECF of brain. The capillary endothelium that lines the choroid plexus consist of open junctions or gaps through which drugs can freely flow into the extracellular space between the capillary wall and the choroidal cells.The blood CSF barrier is formed by the choroidal cell which are joined to each other via tight junctions.
This barrier has permeability characteristic similar to that of BBB.
Only highly lipid soluble drugs can cross the blood-CSF barrier.
Moderately lipid soluble and partially ionized drugs permeate slowly.
A drug that enters into CSF slowly cannot achieve a high concentration, because the bulk flow of CSF continuously removes the drug.
Placental Barrier
The blood vessels of the foetus and mother are separated by a number of tissue layers that collectively constitute the placental barrier. Drugs that traverse this barrier will reach the foetal
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circulation. The placental barrier, like the blood-brain barrier, does not prevent transport of all drugs but is selective and factors that regulate passage of drugs through any membrane (e.g.pKa, lipid solubility, protein binding) are applicable here.
In general, substances those which are lipid soluble cross the placenta with relative ease in accordance with their lipid-water partition coefficient and degree of ionization. Highly polar or ionized drugs do not cross the placenta readily.
Blood-Testis Barrier
The existence of a barrier between the blood and testes is indicated by the absence of staining in testicular tissue after the intravascular injection of dyes. Morphological studies indicate that the barrier lies beyond the capillary endothelial cells and is most likely to be found at the specialized Sertoli-Sertoli cell junction. It appears that Pgp, the efflux transporter protein, plays a role in preventing certain chemotherapeutic agents from reaching specific areas of the testis and hinders the treatment of testis cancer.
II. Blood perfusion rate
The distribution of drugs is limited in two ways such as:-
The drug distribution is permeability rate limited in the case of-
When the drug is ionic, polar or water soluble.
Where the highly selective physiological barriers restrict the diffusion of such drugs to the inside of cells.
The drug distribution is perfusion rate limited when-
The drug is highly lipophilic.
The membrane across which the drug is supposed to diffuse is highly permeable such as those of the capillaries and the muscles.
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Perfusion rate is defined as the volume of blood that flows per unit time per unit volume of the tissue. The rate of blood perfusion to different organs varies widely as shown below in table 1.
Total blood flow is greatest to brain, kidneys, liver, and muscle with highest perfusion rates to brain, kidney, liver, and heart. It would be expected that total drug concentration would rise most rapidly in these organs. Certain organs such as the adrenals (1.2/0.2%) and thyroid (2.4/1%) also have large perfusion rates.
Table 1: Blood perfusion rate.
Organ Perfusion rate (ml/min/ml of tissue) 1. Highly Perfused
Lungs 0.02
Kidneys 4.0
Adrenals 1.2
Liver 0.8
Heart 0.6
Brain 0.5
2. Moderately Perfused
Muscles 0.025
Skin 0.024
2. Poorly Perfused
Fat (adipose) 0.03 Bone (skeleton) 0.02
Examples
The drug thiopental gets into the brain faster than muscle, whereas, penicillin gets into muscle more quickly than it gets into brain.
i. Thiopental is only partly ionized and passes into the brain or muscle easily. Perfusion limits the transport. Since brain has a higher perfusion rate therefore thiopental can transfer in and out more quickly.
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ii. Penicillin is quite polar and is thus slowly permeable. Permeability limited transfer is faster in muscle as muscle capillaries are less restrictive. Thus transfer of penicillin is faster in muscle than brain.
In brain, perfusion or membrane permeability limits drug transport or distribution. Thiopental diffuses readily, thus perfusion limits its distribution. Since perfusion is higher to the brain than to muscle, transport to the brain is faster. Penicillin less readily diffuses thus it is diffusion which limits penicillin distribution. Muscle diffusion is easier thus distribution into muscle is faster for penicillin than distribution into brain.
III. Binding of drugs to tissue components
The drug present in the body can interact with several tissue components, which is divided into two categories-
Blood/ Plasma protein
Extravascular tissue
The detail of drug binding with blood/ Plasma and extravascular tissue are discussed as:- i. Blood/ Plasma
After absorption, the drugs move further either as free drug or bound drug. When the drug exist in the free form it is soluble in the plasma and is transported readily but in bound form the transport becomes limited due to increase size.
The binding of the drug takes place with a variety of proteins present in the plasma like albumin, globulin, lipoprotein and glycoprotein, etc.
There are different types of proteins present in the blood. On the basis of their molecular weight and concentration, they bind with different drugs. The Human serum albumin is the blood protein with the molecular weight of 65000 Da ranges in concentration from
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3.5- 5.0 %, and mostly bind with all type of drugs. Whereas, α-1-acid glycoprotein with molecular weight 44000 and lipoprotein with molecular weight 200000- 3400000 Da binds with basic drugs (imipramine, lidocaine, quinidine). The α1- Globulin (59000) and α2- Globulin (134000) are the two type of globulin protein which binds with steroids (corticosterone, thyroxine), cyanocobolamine (Vitamin B12) and vitamins (A, D, E, K), cupric ions respectively. The protein present in highest concentration (11-16%) with molecular weight 64000 Da known as hemoglobulin bind with phenytoin, pentobarbital and phenothiazines.
The major protein to which most of the drug bind is albumin. It is abundantly present in the body and therefore a number of acidic/ basic drugs bind to it. The next protein to which the drug shows an affinity for binding is glycoprotein followed by lipoprotein.
Globulins havea limited role in binding.
Once the drugs bind to any of the proteins, it affects the distribution, metabolism and elimination process. The pharmacokinetic profile of a bound drug is different from that of the unbound drug. Variation in the pharmacokinetic profile affects the pharmacodynamics properties of the drug. It is only the unbound form of the drug that shows a pharmacological response.
A drug which has an affinity for protein binding will show less concentration of the free drug in the plasma initially when it is administered for the first time. After repeated administration, an increase in the concentration of unbound drug (free drug) will be there due to the saturation of binding sites. This rise in the concentration levels of unbound drug can lead to toxicity in case of drugs having low therapeutic index.
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Characteristics of various proteins affecting drug distribution
Albumin: It is produced by the liver and has a molecular weight of 69000 Da.It is the most abundant plasma protein. It shows a binding affinity for a large variety of drugs which may be weak acids, neutral or basic drugs. The binding of the drugs to albumin is through weak bonds like hydrogen bond, Vander waal’s forces, hydrophobic forces and therefore binding is reversible in most of the cases.
Lipoprotein: The lipidic substances bind to the protein and are termed as lipoprotein. They are present in the low amount as compared to albumin. For binding with lipoprotein, the drugs need to get dissolved in the lipid core of the protein. Therefore, the lipophilicity of drug plays a major role deforming the binding site of this protein. They are classified into low density lipoproteins, high density lipoproteins and very low density lipoproteins.
Globulin: Globulin are another protein to which binding of the drug takes place. There are a number of plasma globulin like α-globulin, β- globulin, γ- globulin. These globulins have a limited role in binding.They show affinity for acidic, basic or neutral drugs but more specificity is for the basic drugs.
Displacement process in plasma protein binding
When two or more drugs are administered simultaneously and all of them show affinity for the same protein but in different magnitude. Then, the one which has more affinity for a particular protein may displace the already bound protein resulting in its increased concentration in the body. For example, the binding of thyroxine to protein is reduced by salicylates. Another example, is when sulphonamides are administered they displace bilirubin from albumin resulting in its increased concentration which might be a problem in conditions like bilirubin encephalopathy. Furthermore, when warfarin and phenoimidazole are given simultaneously,
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warfarin gets replaced by phenoimidazole resulting in its increased concentration in plasma because of which more bleeding takes place in minor injuries.
Binding of drug with blood cells
The drugs mostly bind with RBC.
Hemoglobulin binds with drugs like phenytoin, phenobarbital.
Carbonic anhydrase binds with acetazolamide.
Imipramine binds with the cell membrane of RBC.
ii. Binding of drug component with tissue & extra vascular component
A drugs need to bind with a particular tissue or receptors. So, that a desired therapeutic response can be observed.
In some cases, it has been observed that the concentration of the drug at the site of action is more than that found in other body components like blood and interstitial fluid. As the cell membrane are principally lipoidal in nature. Therefore, they favour easy permeation of lipid soluble drugs because of which accumulation takes place. Receptor binding is observed for water soluble drug.
In most of the cases, the binding phenomenon is a reversible phenomenon as the bonds of binding are weak in nature. In case where binding is irreversible toxicity issue can arise.
A typical example is binding of paracetamol with liver.
A major consequences of binding with tissue is the exclusion of the drug from the blood as the drug is present as a complex. Hence, the concentration of free drug is less as compared to the complex, which leads to the sustained release of free drug. So, the elimination time is also decreased with increase in drug half-life.
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Repeated dosing of this type of drug for longer period of time leads to the increase in concentration at the site of action in the tissue and results in toxicity.
There are number of examples to illustrate the concept of extravascular tissue drug binding. One of the example is metabolites of paracetamol binds with liver irreversibly and leads to hepatic toxicity. Other example of such binding are large intake of imipiramine slows down the perfusion rate of lungs, the long exposure to heavy metals (mercury, lead) leads to its toxicity which initially target the function of kidney. Further, examples are the excess intake of chloroquine produces stinging sensation on the skin, the administration of phenytoin enhances the metabolism of calciferol which leads to the deficiency of vitamin D resulting in the development of osteomalacia in adults. Furthermore, the thiopental has large volume of distribution and enhanced elimination half-life in obese patients due to presence of large fat content.
Factors affecting binding of protein and drugs 1. Drug related factors
a) Physiochemical characteristics of the drug b) Drug concentration
c) Site specific binding/ absorption of drug 2. Protein/ tissue related factors
(a) Physiochemical characteristics of the protein or binding agents (b) Concentration of protein or binding components
(c) Number of binding sites on the binding agents 3. Drug interactions
(a) Competition between the drugs for binding sites (displacement interaction).
(b) Competition between the drug and normal body constituents (c) Allosteric change in protein molecules
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4. Patient- related factors (a) Age
(b) Intersubject variation (c) Disease states
IV. Miscellaneous factors affecting drug distribution 1. Age
Distribution of a drug gets changes with respect to age. The infants have more total body water than adult. So, the volume of distribution is more in infants than that in adults. Therefore, the doses same as adult doses cannot be given to the infants. Thus, lesser doses are given to a child as compared to an adult. Infants also have more fat content so fat soluble drug accumulates and causes adverse effect. The BBB is poorly developed in the child so the drug can easily penetrate it and cause adverse effect in the brain. Also low albumin level in child leads to more free drug concentration.
In older patients a change occurs in the various parameters of the body like plasma protein concentration, body fat, intracellular fluid content, reduced muscle and tissue mass, reduced blood flow to tissues and organs. All these changes can affect the distribution of drug subsequently affecting the absorption of drugs. It has also been found that as a person ages the barrier separating the blood and the brain i.e. the blood brain barrier becomes less intact resulting in increased distribution of the drug into the brain which can result in adverse effects if there is an increase in the concentration.
2. Pregnancy
During pregnancy, the growth of placenta and foetus occurs. In this state a change occurs in the various parameters of the body like body weight, blood flow, concentration of plasma proteins, cellular fluid content etc. It has been found that there is an increase in the extracellular volume
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and total body water which results in increased volume of distribution for hydrophilic drugs.
This can result in reducing the plasma concentration levels of such drugs. During this period there is also an increase in the body fat which results in increasing the volume of distribution for lipophilic drugs.
An alteration in the concentration levels of plasma protein is also observed in case of pregnancy.
A decrease in the concentration of albumin is seen as a result of which the concentration of free drug increases resulting in more distribution to the tissues.
3. Obesity
The body weight of an individual may also affect the drug distribution. Different body weight alters the various constituents of the body like fat content and percentage of lean tissue and water content. An obese individual will have a high content of fat, low content of lean tissue and water.
The opposite will hold true for a thin person. Obese people have a high fat content and therefore they may be able to store more amount of lipophilic drugs as compared to a relatively thin person. It has been found that lipophilic drugs like barbiturates and benzodiazepenes have a prolonged plasma elimination half life.
4. Disease States
A diseased state results in alteration of blood volume, plasma proteins, pH. Like in case of cardiac failure a change occurs in the apparent volume of distribution. It gets reduced due to low tissue perfusion and altered partition between blood and tissue components. Administration of normal dose can therefore result in increased plasma concentration of the drug resulting in toxicity. Eg of drugs is quinidine and lidocaine.
In case of renal problems there is an increased level of acidic substances in the body as a result of which there may be an altered affinity for protein binding in the body. The increased
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concentration of acidic substances may displace the bound drug from the protein resulting in their increased concentration in the body.
In liver diseases there is reduced levels of proteins affecting drug protein binding. Accumulation of substances like bilirubin and other endogenous substances may result in displacement of drugs from the binding sites. It has been found that the unbound fraction of tolbutamide increased by 115% and the levels of phenytoin increased by 40% in cirrohosis .
VOLUME OF DISTRIBUTION
Volume of distribution Vd (apparent volume of distribution) is the hypothetical volume of body fluid that is required to dissolve the amount of drug needed to achieve the same concentration in the blood. The apparent volume of distribution is not a physiological volume. It cannot be lower than blood or plasma volume but for some drugs it can be much larger than body volume. The typical liquid volume in 70 Kg of man is shown in table 2.
Table 2: The typical liquid volume in % (in L for 70 kg man).
Total water 60 % ( 50-80%) 42 L
Intercellular volume 40 % 28 L
Extracellular volume 20 % 14 L
Plasma volume 4% 3 L
Blood volume 8% 5.5 L
The formula used for the measurement of ‘Vd’ is shown below in equation (6) and (7). The list of volume of distribution of some drugs is shown in table 3.
Vd= amount of drug in the body / plasma drug concentration ………..(6)
The unit for apparent volume of distribution islitres/ Kilogram (L / Kg). As body composition changes with age, Vd decreases.
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The Vd may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood by the equation-
Vd = V P + V T (fu/ fut) ………..(7) Where, VP = plasma volume
VT = apparent tissue volume fu = fraction unbound in plasma fut = fraction unbound in tissue
Table 3: The list of volume of distribution of some drugs.
Drugs Vd(L/Kg) Sulfisoxazole 0.16
Phenytoin 0.63
Phenobarbital 0.55
Diazepam 2.4
Digoxin 7
Some drugs cannot enter into the cells because of their low lipid solubility. These drugs are distributed throughout the body water in the extracellular compartment and have a relatively small Vd. Drugs that accumulate in organs either by active transport or by specific binding to tissue molecules have a high volume of distribution, which can exceed several times the anatomical body volume. Therefore, Vdshould not be identified too closely with a particular anatomical compartment. Lipid-soluble drugs are stored in fat. Bone is a reservoir for drugs such as tetracycline and heavy metals.
Summary
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In the process of drug distribution after entry of drugs into systemic circulation by different routes including intravascular injection or oral administration or any of the various extravascular sites, the drug enters into a number of processes called disposition processes. This process involves distribution and elimination of drugs in and from the body.
Factors affecting distribution of drugs were also explained in detail, as how these factors affect the distribution and absorption of drugs in the body which involves tissue membrane permeability of drugs, physiochemical properties of drug (molecular size, lipid solubility, protein binding), physiological barriers (simple capillary endothelial barrier, simple cell membrane barrier, blood-brain barrier, blood cerebro-spinal fluid barrier, placental barrier), blood perfusion rate, binding of drug to tissue component (binding of drugs to blood, binding of drugs to extravascular components) and other miscellaneous factors like age, pregnancy, obesity, diet, diseased state and drug interaction).
The volume of distribution Vd (apparent volume of distribution) is the hypothetical volume of body fluid that would be required to dissolve the amount of drug needed to achieve the same concentration in the blood.
