Drug distribution is the process by which a drug moves between the blood and various tissues (e.g., muscle and fat) or organs (e.g., brain).
It is an integral part of ADME (absorption, distribution, metabolism, and excretion), which encompasses the complete fate of a drug when it enters the body – pharmacokinetics.
Many factors can influence the ability of a drug to distribute in the body, including physicochemical and physiological factors and the contribution of transporters.
Factors Affecting Drug Distribution
Water and Fat Solubility:
A water-soluble drug will tend to stay in the blood or interstitial spaces.
A fat-soluble drug may concentrate in fatty tissues.
Barriers:
Drugs can be limited by their ability to cross barriers, such as the blood–brain barrier (BBB) or placental barrier.
Plasma Protein Binding:
Drug binding to plasma proteins can affect its ability to distribute.
Bound drug is not able to distribute into tissues; only the fraction unbound (free) moves into tissues and determines the pharmacodynamics or efficacy of the drug.
Classification of Drugs Based on Solubility
Lipophilic (Fat Soluble):
Nonpolar compounds
Easily diffuse across lipid bilayers of cell membranes
Can be administered topically
Free diffusion across the blood-brain barrier
Biotransformed in the liver
Excreted through the bile duct
Hydrophilic (Water Soluble):
Polar compounds
Cross lipid bilayers via facilitated transport (passive chemical diffusion across a cell membrane by ion channels or carriers)
Eliminated by kidneys
Process of Distribution
Once a drug is absorbed into the bloodstream it can be carried throughout the body.
It is a reversible process - some molecules may be interacting with receptors on cell membranes or inside cells other molecules may move back into the bloodstream.
Factors affecting the delivery of a drug:
Blood flow
Capillary permeability
Degree of binding (attachment) of the drug to blood and tissue proteins
Relative lipid-solubility of the drug molecule
Body Compartments
Each drug distributes differently and not equally to all regions of the body.
These regions are also known pharmacokinetically as compartments.
Each drug when it enters the systemic circulation can enter one of 3 main body compartments or be sequestered at a particular site.
The drug also can remain sequestered within tissues such as bone, adipose tissue, or indeed the foetus.
Body Water Distribution
The adult human body is about 60% water.
Therefore, the body of an average adult who weighs 70 kg (about 150 lbs) contains 42 L of water.
The fluid contained in the bloodstream makes up about 5 L, or about 9% of the volume of an average sized adult.
The total water outside of the cells (extracellular fluid) includes the plasma volume plus the fluid in the interstitial space and is about 14 L.
Intracellular fluid makes up the remaining 28 L.
Drugs with high molecular weights or drugs that are extremely hydrophilic (with a strong affinity for water) tend to stay within the circulatory system and organs with a rich blood supply and have a smaller apparent volume of distribution.
Small, highly lipophilic drugs have a large apparent volume of distribution.
Drug Distribution as a Dynamic Phenomenon
As soon as the drug enters the systemic circulation, some of the drug will already be undergoing the irreversible drug elimination phase while distribution occurs elsewhere.
Drug distribution Is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and then the cells or the tissues.
For a drug administered IV when absorption is not a factor the initial phase represents the distribution phase during which a drug rapidly disappears from the circulation and enters the tissues
This is followed by the elimination phase when drug in the plasma is in equilibrium with drug in the tissues.
The delivery of a drug from the plasma to the interstitium primarily depends on cardiac output and regional blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins and the relative hydrophobicity of the drug.
Factors Influencing Drug Distribution
A) Blood Flow
The rate of blood flow to the tissue capillaries varies widely because of the unequal distribution of cardiac output to the various organs.
Blood flow to the brain, liver and kidney is greater than that to the skeletal muscles.
Adipose tissue, skin and viscera have still lower rates of blood flow.
E.G. High blood flow together with the high lipid solubility of thiopental (anaesthetic) permits it to rapidly move into the CNS and produce anaesthesia.
A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration sufficiently so that the higher concentration within the CNS decreases and consciousness is regained.
B) Capillary Permeability
Capillary permeability is determined by capillary structure, it varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells
In the liver and spleen a large part of the basement membrane is exposed due to large discontinuous capillaries through which large plasma proteins can pass.
This contrasts with the brain where the capillary structure is continuous and there is no slit junctions.
To enter the brain drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported.
For example, a specific transporter for the large neutral amino acid transporter carries levodopa into the brain (levodopa is a drug to treat Parkinson's disease).
By contrast lipid soluble drugs readily penetrate the CNS because they can dissolve in the membrane of the endothelial cells.
Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS.
These tightly juxtaposed (close together) cells form tight junctions that constitute the so-called blood brain barrier.
Note: This barrier is an adaptation that for the most part protects brain tissue from invasion by foreign substances.
To readily penetrate the brain, drugs must be fairly small and lipid soluble or must be picked up by the carrier-mediated transport mechanism in the central nervous system.
This explains why the small and highly fat-soluble anaesthetic gases quickly and easily penetrate the brain to cause anaesthesia, while other larger and water-soluble molecules like penicillin antibiotics penetrate the central nervous system to a much lesser degree.
C) Binding of Drugs to Plasma Protein and Tissues
1. Bindings to Plasma Proteins:
Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment.
Binding is relatively non-selective regarding chemical structure and takes place at sites on the protein to which endogenous compounds such as bilirubin normally attach.
Plasma albumin is the major drug binding protein and may act as a drug reservoir (that is as the concentration of the free drug decreases due to elimination by metabolism or excretion the bound drug dissociates from the protein).
This maintains the free drug concentration as a constant fraction of the total drug in the plasma.
Binding to plasma proteins affects drug distribution into tissues, because only drug that is not bound is available to penetrate tissues, bind to receptors, and exert activity.
As free drug leaves the bloodstream, more bound drug is released from binding sites.
In this way, drugs maintain a balance between free and bound drug that is unique to each compound, based on its affinity for plasma proteins.
Albumin, then, acts as a reservoir of an administered drug.
Some drugs have a high affinity for binding to serum proteins and may be 95% to 98% protein bound.
With highly protein bound drugs, low albumin levels (as in protein-calorie malnutrition, or chronic illness) may lead to toxicity because there are fewer than the normal sites for the drug to bind.
The amount of free drug is significantly increased in that case.
The physician or pharmacist must consider the patient’s serum albumin level when the dose of a highly protein bound medication is selected.
Only free and unbound drugs will pass from vascular spaces to tissues where a drug-receptor interaction will occur as well as the effect of the drug.
2. Binding to Tissue Proteins:
Numerous drugs accumulate in tissues leading to higher concentrations of the drug in tissues than in the extracellular fluids and blood.
Drugs may accumulate as a result of binding to lipids, proteins or nucleic acids.
Drugs may also be actively transported into tissues.
These tissue reservoirs may serve as a major source of the drug and prolong its actions or can cause local drug toxicity.
Competition for binding sites is one important way that drugs might interact.
If a patient is using two highly protein bound drugs at the same time, there will be competition for binding sites on the albumin.
The drug with the greatest affinity for the albumin will bind, and is thought to disrupt the normal ratio of free to bound drug for the second medication.
As a result, the second medication will be more available to distribute to the site of action and potentially cause side effects.
3. Hydrophobicity:
The chemical nature of a drug strongly influences its ability to cross cell membranes.
Hydrophobic drugs readily move across most biologic membranes.
These drugs can dissolve in the lipid membrane and therefore permeate the entire cells surface.
The major factor influencing the hydrophobic drugs distribution is the blood flow to the area.
By contrast hydrophilic drugs do not readily penetrate cell membranes and must pass through the slit junctions.
Blood flow to different organs of the body is not equal.
The most vitally important organs of the body receive the greatest supply of blood.
These organs include the brain, liver, and kidneys.
Skeletal muscle and bone receive less blood, and adipose tissue (fat) receives the least.
If blood flow were the only factor affecting distribution, it would be reasonable to expect that high concentrations of administered medications would always appear in the brain and liver.
In reality, few drugs exhibit good penetration of the central nervous system.
Drug Factors Affecting Distribution
Molecular Size of Drug
Drugs with a small molecular size are generally more widely distributed than large drugs.
Ionization of Drug
Drug is less likely to be well distributed if they are ionized – often due to the phenomenon of Ion Trapping.
Degree of Lipid Solubility
The higher the lipid solubility then the more likely the drug will be well distributed – lipid drugs even cross the blood-brain barrier.
Binding of Drugs to Plasma Proteins
Drugs must remain in the unbound form to be well distributed and elicit a pharmacodynamic response.
*Plasma Protein
Prolongation Bound drug may be slowly released thereby increasing the half-life of the drug, this becomes important for drugs with low therapeutic indexes.
Volume of Distribution
The apparent volume of distribution (Vd) can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in plasma.
It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0).
V<em>d=C</em>0Amount of drug in the body
Though Vd has no physiologic or physical basis it can be useful to compare the distribution of a drug with the volumes of the water compartments in the body.
For a drug that is highly tissue-bound, very little drug remains in the circulation; thus, plasma concentration is low and volume of distribution is high.
Drugs that remain in the circulation tend to have a low volume of distribution.
Volume of distribution provides a reference for the plasma concentration expected for a given dose but provides little information about the specific pattern of distribution.
Each drug is uniquely distributed in the body.
Some drugs distribute mostly into fat, others remain in extracellular fluid, and others are bound extensively to specific tissues.
Many acidic drugs (e.g., warfarin, aspirin) are highly protein-bound and thus have a small apparent volume of distribution.
Many basic drugs (e.g., amphetamine, meperidine) are extensively taken up by tissues and thus have an apparent volume of distribution larger than the volume of the entire body.
The most commonly used volumes of distribution are:
Central volume (Vc) - Vc=Peak serum levelDose
Tissue (or peripheral) volume (Vt)
Apparent volume of distribution (Vd)
The fact that drug clearance is usually a first order process allows calculation of Vd (first order means that a constant fraction of drug is eliminated per unit of time).
This can be easily analysed by plotting the log of the plasma drug concentration (Cp) versus time.
The concentration of drug in plasma can be extrapolated back to time zero on the Y axis to determine C0
Distribution into Water Compartments of the Body
Once a drug enters the body from whatever route of administration it has the potential to distribute into any one of 3 functionally distinct compartments of body water or to become sequestered in a cellular site.
A) plasma compartment: if a drug has a very large molecular weight or binds extensively to plasma proteins it is too large to move out through the endothelial slit junctions of the capillaries and thus is effectively trapped within the plasma compartment.
As a consequence the drug distributes in a volume that is about 6% of the body weight or in a 70kg individual about 4 L of body fluid.
B) extracellular fluid: if a drug has a low molecular weight but is hydrophillic it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the lipid membranes to enter the water inside the cell.
Therefore, these drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid which together constitute the extracellular fluid. This is about 20 % of the body weight or about 14 L in a 70 kg person. Aminoglycoside antibiotics show this type of distribution.
C) Total body water: if a drug has a low molecular weight and is hydrophobic not only can it move into the interstitium through the slit junctions it can also move through cell membranes into the intracellular fluid.
The drug distributes into a volume of about 60% of body weight or about 42L in a 70 kg person. Ethanol exhibits this apparent volume of distribution.
Apparent volume of distribution
A drug rarely associates exclusively with only one of the water compartments of the body. Instead most drugs distribute into several compartments often avidly binding cellular components such as lipids, proteins and nucleic acids. Therefore, the volume into which drugs distribute is called the apparent volume of distribution (Vd).
Vd is a useful pharmacokinetic parameter for calculating a drugs loading dose.
Effect of Vd on drug half-life
A large Vd has an important influence on the half-life of a drug because drug elimination depends on the amount of drug delivered to the liver or kidney per unit of time.
Delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of the drug in the plasma.
If the Vd for a drug is large most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases Vd can lead to an increase in the half -life and extend the duration of action of the drug.
Drug Half-Life
Half-life (t1/2) refers to the time required for plasma concentration of a drug to decrease by 50%.
T1/2 is dependent on the rate constant (k), which is related to Vd & clearance (CL)
Half-life can be expressed using the following equation(s):
Half-life (hours) = 0.693×(Clearance (L/hr)Volume of distribution (L))
Only the drug located in the central compartment can be eliminated from the body because the process of elimination is primarily carried out by the liver and kidneys.
Drugs with a high Vd will have a large fraction of drug remaining outside of the central compartment.
Meanwhile, the fraction of drug in the plasma will be eliminated, causing a shift of equilibrium resulting in drug located in the peripheral compartment to shift into the central compartment.
This shift will cause the plasma concentration to remain at a steady-state concentration despite drug removal from the body.
This phenomenon causes plasma concentration to decline more slowly during the elimination phase in the setting of a high Vd
Therefore, at a constant rate of clearance, a drug with a high Vd will have a longer elimination half-life than a drug with lower Vd.
Like the different Vd values that exist depending on the pharmacokinetic phase, there are also two half-life values of which it is important to be aware:
The distribution half-life (t1/2a) which represents the amount of time required for the plasma concentration to decline by 50% during the distribution phase.
The elimination half-life (t1/2b) which represents the amount of time required for the plasma concentration to decline by 50% during the elimination phase.
Drug Clearance Through Metabolism
Once a drug enters the body the process of elimination begins.
The 3 major routes involved are:
Hepatic metabolism
Elimination in the bile
Elimination in urine
These elimination processes cause the plasma concentration of a drug to decrease exponentially.
That is at any given time a constant fraction of the drug present is eliminated in a unit of time.
Most drugs are eliminated according to first order kinetics although some such as aspirin in high doses are eliminated according to zero order kinetics or nonlinear kinetics.
Metabolism leads to products with increased polarity (water soluble) which will allow the drug to be eliminated.
Clearance
Clearance (CL) estimates the amount of drug cleared from the body per unit of time.
Total clearance is a composite estimate reflecting all mechanisms of drug elimination and is calculated as:
CL=t1/20.693×Vd
Where t1/2 is the drugs elimination half life, Vd is the apparent volume of distribution and 0.693 is the natural log constant.
Drug half life is often used as a measure of CL because for many drugs V d is a constant.
Half-life (t1/2) of a drug is the time required to reduce the drug concentration by half.
Km is the Michaelis-Menten constant - is the substrate concentration at half the maximum velocity (Vmax)
Kinetics of Metabolism
1. First Order Kinetics:
The metabolic transformation of drugs is catalyzed by enzymes and most of the reactions obey Michaelis-Menten kinetics
V=rate of drug metabolism=K</em>m+[C]V<em>max[C]
In most clinical situations the concentration of the drug [C] is much less than the Michaelis constant Km and the Michaelis-Menten equation reduces to:
V=K</em>mV<em>max[C]
The rate of drug metabolism and elimination is directly proportional to the concentration of free drug and first order kinetics are observed.
This means that a constant fraction of the drug is metabolised per unit of time that is with every half-life the concentration reduces by 50%.
First order kinetics is sometimes referred to clinically as linear kinetics.
2. Zero-Order Kinetics:
With a few drugs such as aspirin and ethanol the doses are very large.
Therefore [C] is much greater than Km and the velocity equation becomes
V=[C]V<em>max[C]=V</em>max
The enzyme is saturated by a high free drug concentration and the rate of metabolism remains constant over time.
A constant amount of a drug is metabolised per unit of time and the rate of elimination is constant and does not depend on the drug concentration.
Zero-order process takes place at a constant rate independent of the existing concentration or initial concentration.
E.G.: A patient was given 100 mg of drug A orally. Assume that the drug absorption follows zero-order kinetics at a rate of 10 mg/min. Then can you predict the drug absorption at every minute?
For every minute, 10 mg of the drug will undergo absorption. So after 5 minutes, how much will be absorbed?
5 x 10 mg = 50 mg will be absorbed.
Similarly, 80 mg will be absorbed after 8 minutes.
By what time the whole drug will be absorbed? it will take 10 minutes for complete absorption of drug and the process comes to an end.
If the administered dose of the same drug is 200 mg, again the same rate, 10 mg/min will be followed, and the process comes to an end after 20 mins.
Reactions of Drug Metabolism
The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules.
Therefore, lipid-soluble agents must first be metabolised into more polar (hydrophilic) substances in the liver using two general sets of reactions called phase I and phase II.
Phase I
Phase I reactions convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group such as –OH or –NH2.
Phase I metabolism may increase, decrease or leave unaltered the drugs pharmacologic activity.
Phase I reaction use the P450 enzyme system.. Or are catalysed by the P450 system.
Also known as the microsomal mixed function oxidase.
The P450 system is important for the metabolism of many endogenous compounds (such as steroids, lipids, etc) and for the biotransformation of exogenous substances (xenobiotic).
Cytochrome P450 designated as CYP is a superfamily of heme containing isozymes that are in most cells but are primarily found in the liver and GI tract.
The family name is indicated by CYP added to Arabic number followed by a capital letter for the subfamily e.g., CYP3A.
Another number is added to indicate the specific isozyme as in CYP3A4.
Because there are many different genes that encode multiple enzymes there are likewise many different P450 isoforms.
These enzymes have the capacity to modify many structurally diverse substrates.
In addition, an individual drug may be a substrate for more than one isozyme.
Four isozymes are responsible for the vast majority of P450 catalysed reactions. They are CYP3A4/5, CYP2D6, CYP2C8/9 and CYP1A2.
Considerable amounts of CYP3A4 are found in intestinal mucosa – first pass metabolism for drugs e.g., chlorpromazine
P450 enzymes exhibit considerable genetic variability among individuals and racial groups.
Variations in P450 activity may alter a drug's efficacy and the risk of adverse events.
CYP2D6 has been shown to exhibit genetic polymorphism.
CYP2D6 mutations result in very low capacities to metabolise substrates.
Some people obtain no benefit from the opioid analgesic codeine because they lack the CYP”D6 enzyme that activates this drug.
The frequency of this polymorphism is in part racially determined, with a prevalence of 5-10% in EU Caucasians as compared to less than 2% of Southeast Asians.
With prodrugs such as Clopidogrel CYP2C19 is required to convert it to an active metabolite.
The CYP 450 dependent enzymes are an important target for pharmacokinetic drug interactions.
One such interaction is the induction of selected CYP isozymes.
Xenobiotic (chemicals not normally produced or expected to be present in the body) may induce the activity of these enzymes by inducing the expression of the genes encoding the enzymes.
Certain drugs e.g., phenobarbital can increase the synthesis of one or more CYP isozymes.
This results in increased biotransformation of drugs and can lead to significant decreases in plasma concentration of drugs metabolised by these CYP isozymes with concurrent loss of pharmacologic effect.
Consequences of Increased Drug Metabolism
decreased plasma drug concentrations
decreased drug activity if the metabolite is inactive
increased drug activity if the metabolite is active (prodrug)
decreased therapeutic drug effect
Inhibitors
Inhibition of CYP isozyme activity is an important source of drug interactions that lead to serious adverse events.
The most common form of inhibition is through competition for the same isozyme.
Some drugs are capable of inhibiting reactions for which they are not substrates leading to drug interactions.
Numerous drugs have been shown to inhibit one or more of the CYP dependent biotransformation pathways of warfarin.
If the two drugs are taken together plasma concentration of warfarin increase which leads to greater inhibition of coagulation and risk of haemorrhage and other serious bleeding reactions.
Natural substances may also inhibit drug metabolism. Eg. Grapefruit juice inhibits CYP3A4 drugs such as nifedipine which is metabolised by this isozyme causing it to persist in the blood system and an increase in the drugs effect
Phase I reactions not involving the P450 system – these include amine oxidation, alcohol dehyrogenation, esterases and hyrolysis
Phase II: Phase II consists of conjugation reactions.
Phase II
If the metabolite from Phase I metabolism is sufficiently polar it can be excreted by the kidneys.
But many Phase I metabolites are to lipophilic to be retained in the kidney tubules.
A subsequent conjugation reaction with an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid or an amino acid results in the formation of more polar compounds which can be excreted.
Glucuronidation
Glucuronidation (joining to glucuronic acid) is the most common and the most important conjugation reaction.
Neonates are deficient in this conjugating system making them particularly vulnerable to drugs e.g., chloramphenicol (antibiotic) and gray baby syndrome.
Note: not all drugs undergo Phase I and phase II metabolism in that order e.g. isoniazid is first acetylated (phase II) then hydrolysed to isonicotinic acid (phase I).
Additional Factors Affecting Distribution of Drugs