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1 FACTORS AFFECTING DISTRIBUTION OF DRUG Dr. Shubhrajit Mantry D.Pharm, B.Pharm, M.Pharm, Ph.D Associate Professor Department of Pharmaceutics, Sharadchandra Pawar College of Pharmacy, Pune, Maharashtra, India


2 After entry into the systemic circulation, either by intravascular injection or by absorption from any of the various extravascular sites, the drug is subjected to a number of processes called as disposition processes. Disposition is defined as the process that tend to lower the plasma concentration of drug. The two major drug disposition processes are as : Distribution: Which involves reversible transfer of a drug between compartments. Elimination: Which causes irreversible loss of drug from the body. Elimination is further divided into two processes: a) Biotransformation (metabolism) b) Excretion


3 The interrelationship between drug distribution, biotransformation and excretion and the drug in plasma is shown in figure. Figure 1: The interrelationship between different process of drug disposition


4 Drug Distribution is defined as the Reversible transfer of drug between one compartment (blood) to another (extra vascular tissue) DISTRIBUTION


5 STEPS IN DRUG DISTRIBUTION Distribution of drug present in systemic circulation to extravascular tissues involves following steps: Permeation of free or unbounded drug present in the blood through the capillary wall (occur rapidly) and entry into the interstitial/extracellular fluid (ECF) Permeation of the drug present in the ECF through the membrane of tissue cells and into the intercellular fluid. This step is rate limiting and depend upon two major factors: a) Rate of Perfusion to the ECF b) Membrane Permeability of the Drug


6 FACTORS AFFECTING DISTRIBUTION OF DRUGS Tissue Permeability of Drugs a) Physicochemical Properties of drug like: Molecular size, pK a, o/w Partition Coefficient b) Physiological barriers to diffusion of drugs Organ/tissue size and perfusion rate Binding of drugs to tissue components. a) Binding of drug to blood components b) binding of drug to extra cellular components Miscellaneous a) Age b) Pregnancy c) Obesity d) Diet e) Disease states f) Drug interactions


7 TISSUE PERMEABILITY OF DRUGS The tissue permeability of a drug depends upon the physicochemical properties of the drug as well as the physiologic barriers that restrict diffusion of drug into tissues.


8 Physicochemical Properties of drug s of the drug Molecular size, pKa o/w Partition Co Efficient. Physiological barriers to Distribution of Drugs Simple Capillary Endothelial Barrier Simple Cell Membrane Barrier Blood Brain Barrier Blood – CSF Barrier Blood Placental Barrier Blood Testis Barrier


9 a) Physicochemical Properties of the Drug Important physicochemical properties that influence its distribution are molecular size, degree of ionization, partition coefficient. Almost all drugs having molecular weight less than 500 to 600 Daltons easily cross the capillary membrane to diffuse into the extracellular interstitial fluids. However, penetration of drugs from the extracellular fluid into the cells is a function of molecular size, ionization constant and lipophilicity of the drug. Only small, water-soluble molecules and ions of size below 50 Daltons enter the cell through aqueous filled channels whereas those of larger size are restricted unless a specialized transport system exists for them. MOLECULAR SIZE




11 The degree of ionization of a drug is an important determinant in its tissue penetrability. The pH of the blood and the extravascular fluid also play a role in the ionization and diffusion of drugs into cells. A drug that remains unionized at these pH values can permeate the cells relatively more rapidly. Since the blood and the ECF pH normally remains constant at 7.4, they do not have much of an influence on drug diffusion unless altered in conditions such as systemic acidosis or alkalosis. DEGREE OF IONIZATION


12 Most drugs are either weak acids or weak bases and their degree of ionization at plasma or ECF pH depends upon their pKa. All drugs that ionise at plasma pH (i.e. polar, hydrophilic drugs), cannot penetrate the lipoidal cell membrane and tissue permeability is the rate- imiting step in the distribution of such drugs. Only unionized drugs which are generally lipophilicity, rapidly cross the cell membrane. Among the drugs that have same o/w partition coefficient but differ in the extent of onization at blood pH, the one that ionizes to a lesser extent will have greater penetrability than that which ionizes to a larger extent; for example, pentobarbital and salicylic acid have almost the same Ko /w but the former is more unionized at blood pH and therefore distributes rapidly. pK a, o/w Partition Coefficient In case of polar drugs where permeability is the rate-limiting step in the distribution, the driving force is the effective partition coefficient of drug. It is calculated by the following formula: Effective Ko/w = (Fraction unionsied at pH 7.4) (Ko/w of unionsied drug)


13 Physiological barriers to Distribution of Drugs: Simple Capillary Endothelial Barrier Simple Cell Membrane Barrier Blood Brain Barrier Blood – Cerebrospinal fluid Barrier Blood Placental Barrier Blood Testis Barrier


14 Simple Capillary Endothelial Barrier The membrane of capillaries that supply blood to most tissues. All drugs, ionised or unionised, with a molecular size less than 600 Daltons, diffuse through the capillary endothelium and into the interstitial fluid. Only drugs that bound to that blood components can’t pass through this barrier Because of larger size of complex.


15 Simple Cell Membrane Barrier once the drug diffuses from capillary wall into the extracellular fluid, its further entry in to cells of most tissue is limited. . Simple cell Membrane is similar to the lipoidal barrier (absorption) Non polar & hydrophillic drugs will passes through it (passively). Lipophilic drugs with 50-600 Dalton molecular size & Hydrophilic, Polar drugs with ‹50dalton will pass this membrane.


16 Blood Brain Barrier capillaries found in other parts of the body, the capillaries in the brain are highly specialized and much less permeable to water-soluble drugs. The brain capillaries consist of endothelial cells which are joined to one another by continuous tight intercellular junctions comprising is called as the blood-brain barrier.


17 A solute may cross to brain via only one of the two pathway: Passive diffusion through the lipoidal barrier: Which restricted to smaller molecules (with a molecular weight less than 700 Daltons) having high o/w partition coefficient. Active transport of essential nutrients such as sugars and amino acid. Thus structurally similar foreign molecules can also penetrate the BBB by the same mechanism. Approaches of BBB Three different approaches have been utilized successfully to promote crossing the BBB by drugs: Use of permeation enhancer: Dimethyl sulphoxide (DMSO) Osmotic disruption of the BBB by infusing internal carotid artery with mannitol . Use of dihydropyridine redox system as drug carriers to the brain.


18 Blood – Cerebrospinal fluid Barrier The cerebrospinal fluid (CSF) is formed mainly by the choroid plexus of the lateral, third and fourth ventricles and is similar in composition to the ECF of brain. The capillary endothelium that lines the choroid plexus have open junctions or gaps and drugs can flow freely into the extracellular space between the capillary wall and the choroidal cells. However, the choroidal cells are joined to each other by tight junctions forming the blood-CSF barrier which has permeability characteristics similar to that of the BBB


19 As in the case of BBB, only highly lipid soluble drugs can cross the blood-CSF barrier with relative ease whereas moderately lipid soluble and partially ionized drugs permeate slowly. A drug that enters the CSF slowly cannot achieve a high concentration as the bulk flow of CSF continuously removes the drug. For any given drug, its concentration in the brain will always be higher than in the CSF.


20 Blood Placental Barrier


21 The maternal and the fetal blood vessels are separated by a number of tissue layers made of fetal trophoblast basemen membrane and the endothelium which together constitute the placental barrier. The human placental barrier has a mean thickness of 25 microns in early pregnancy that reduces to 2 microns at full term which however does not reduce its effectiveness. Many drugs having molecular weight less than l000 daltons and moderate to high lipid solubility e.g. ethanol, sulfonamides, barbiturates, gaseous anesthetics, steroids, narcotic analgesics, anticonvulsants and some antibiotics, cross the barrier by simple diffusion quite rapidly.


22 Drug can affect the foetus at 3 stages as shown in Table: An agent that causes toxic effect on foetus is called as teratogen. Teratogenecity is defined as foetal abnormalities caused by administration of drug during pregnancy.


23 Blood Testis Barrier This barrier is located not at the capillary endothelium level but at sertoli-sertoli cell junction. It is the tight junctions between the neighboring sertoli cells that act as the blood-testis barrier. This barrier restricts the passage of drugs to spermatocytes and spermatids.


24 Distribution is permeability rate - limited in following cases: When the drug is ionic/polar/water soluble Where the highly selective physiology barrier restrict the diffusion of such drugs to the inside of cell. Distribution will be perfusion rate - limited When the drug is highly lipohilic When the membrane is highly permeable . 2. ORGAN/TISSUE SIZE AND PERFUSION RATE Whereas only high lipophilic drugs such as thiopental can cross the most selective passage of the barriers like the BBB, highly permeable capillary wall permits passage of almost all drug (except those bound to plasma proteins)


25 Perfusion rate is defined as the volume of the blood that flows per unit time per unit volume of the tissue. Unit: ml/min/ml (Distribution Rate Constant) Kt = perfusion rate / K t/b The tissue distributed half-life is given by equation: Distribution half life = 0.693/Kt =0.693K t/b /perfusion rate K t/b tissue/blood partition coefficient


26 3. BINDING OF DRUGS TO TISSUE COMPONENTS Binding of drugs to blood components Plasma proteins Blood cells b) Binding of drugs to extra vascular tissues

3).Binding of drug to tissue components:

3).Binding of drug to tissue components a) Binding of drug to blood components;- i) Plasma protein bindings Human serum albumin :-all types drug ά 1- acid glycoprotein :-basic drugs(impr) Lipoproteins :-basic,lipophilic drugs (chlorpromazin ) ά 1- Globuline :-steroids like corticosterone ,vit-B12 ά 2- Globuline :-vit-A,D,E,K,cupric ions. Hemoglobin :-Phenytoin, phenothiazines. ii) Blood cells bindings:- RBC : 40% of blood comprise of blood cells out of that 95% cells are RBC (RBC comprise of hemoglobin) drugs like , phenytoin,phenobarbiton binds with Hb ,imipramine,chlorpromazine binds with RBC Cell wall

Binding of drugs to blood cells :

Binding of drugs to blood cells The major component of blood is RBC The RBC comprises of 3 components each of which can bind to drugs: Hemoglobin Carbonic Anhydrase Cell Membrane

Binding of drugs to plasma proteins:

Binding of drugs to plasma proteins The binding of drug to plasma protein is reversible The extent or order of binding of drugs to various plasma proteins is: Albumin > α 1 -Acid Glycoprotein> Lipoproteins > Globulins Human Serum Albumin (HSA) Most abundant plasma protein with large drug binding capacity Both endogenous compounds and drugs bind to HSA Four different sites on HSA: Site I: warfarin and azapropazone binding site Site II: diazepam binding site Site III: digitoxin binding site Site IV: tamxifen binding site

3).Binding of drug to tissue components:

3).Binding of drug to tissue components B. Extra Vascular Tissue proteins 40% of total body weight comprise of vascular tissues Tissue-drug binding result in localization of drug at specific site in body and serve as reservoir As binding increases it also increase bio-logical half life. Irreversible binding leads to drug toxicity. ( carbamazepin -auto induction) liver > kidney > lungs > muscle > skin > eye > bone > Hair, nail

Miscellaneous factors :

Miscellaneous factors 4). Miscellaneous Factors Age: Total body water Fat content Skeletal muscles Organ composition Plasma protein content Pregnancy Obesity Diet Disease states

4). Miscellaneous factors:

4). Miscellaneous factors a) AGE:- Difference in distribution pattern of a drug in different age groups are mainly due to differences in: a) Total body water -(both Intracellular & Extracellular) greater in infants b) Fat content – It is also higher in infants & in elderly c) Skeletal muscle – are lesser in infants & in elderly d) organ composition – BBB is poorly developed in infants & myelin content is low & cerebral blood flow is high , hence greater penetration of drug in brain e) plasma protein content- low albumin content in both infants & in elderly


33 B) PREGNANCY:- During Pregnancy, due to growth of UTERUS,PLECENTA,FETUS increases the volume available for distribution drug. The plasma & ECF Volume also increase but albumin content is low . C) OBECITY :- In obese persons, high adipose (fatty acid) tissue so high distribution of lipophilic drugs.

4). Miscellaneous factors:

4). Miscellaneous factors d) DIET:- A diet high in fats will increases free fatty acid levels in circulation thereby affecting binding of acidic drugs (NSAIDs to albumin) e) DISEASE STATES:- A number of mechanism involved in alteration of drug distribution in disease states. Altered albumin & other drug-binding protein concentration. Alteration or reduced perfusion to organ or tissue Altered tissue pH. Alteration of permeability of physiological barrier (BBB) EX- BBB (in meningitis & encephalities ) BBB becomes more permeable polar antibiotics ampicilin , penicilin G. & patient affect CCF , Perfusion rate to entire body decreases it affect distribution. f) DRUG INTERACTION:- Drug interaction that affect distribution are mainly due to differenence in plasma protein or tissue binding of drugs. Ex. A. Warfarin (Displaced Drug) & B. Phenylbutabutazone (Displacer) HSA



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