Distribution is the second step in drug pharmacokinetics. Pharmacokinetics refers to how a drug is processed by the body. Volume of distribution is a way to quantify the extent of drug distribution throughout the body.
Intravascular & Extravascular Spaces
How a drug distributes throughout the body is dependent on a number of factors including:
- Physical properties of the drug:
- acidic/basic/lipophilic/hydrophilic
- This can affect the degree of protein binding and its ability to cross physiological barriers like the blood brain barrier, blood-placenta barrier and blood-gas barrier .
- Concentration of drug transporters in the blood:
- Drug transporters include proteins like albumin, alpha1acid glycoprotein and lipoprotein
- Body fat composition:
- Lipophilic drugs are fat loving and will concentrate in those areas
- Body water distribution:
- Hydrophilic drugs are water loving and will be affected by any condition that alters body fluid composition
- Presence of disease:
- Physiological conditions like burns, third spacing, congestive heart failure and dehydration can alter drug distribution
Volume of Distribution
An important concept for understanding the distribution of drug once it is absorbed is the volume of distribution. Before I define it, let me explain why it is needed (it makes more sense this way).
When a drug enters systemic circulation it is suspended in plasma along with red blood cells, white blood cells, platelets, proteins and everything else that makes up blood. We can measure the amount of drug in plasma by collecting a sample and quantifying it.
However, the amount of drug in plasma is not the only drug present in the body. At the time a blood sample is collected there is drug in tissues and organs like the brain, the lungs, liver and fat. Therefore the quantification of drug in the body from a blood sample is not a truly accurate representation of the amount of drug in the whole body.
Volume of distribution attempts to quantify the degree to which a drugs distribution extends beyond plasma volume (~3L). It indicates the tendency of a drug to remain in the blood or distribute into body tissue.
A drug with a high volume of distribution will have a low plasma volume because it is accumulating in organs and tissues.
A drug with a low volume of distribution will maintain a high plasma concentration.
Calculating Vd
Volume of distribution is measured in liters, just like plasma volume. It is calculated simply by dividing the amount of drug given (mg) by the measured plasma concentration (mg/L).
The average plasma volume is ~3L. If a drug has a high volume of distribution its quantification will exceed 3L. If it has a low volume of distribution it will be at least less than 3L.
One vs Multicompartment Models
The equation above represents the simple calculation of volume of distribution which considers the body to be a single compartment i.e. one bucket, in which equilibrium between the intravascular space and the extravascular space occurs instantaneously. It is most applicable to highly perfused tissues like the liver and kidney.
This assumption is why the equation above showing a direct and inverse relationship between plasma concentration and volume of distribution works.
However, most drugs will not follow this single compartment model. The multicompartment model assumes distribution into multiple “body buckets” each with their own properties.
Lets assume 3 buckets: plasma bucket, fat bucket, muscle bucket.
The Body Bucket Approach
A drug can distribute into all these buckets. The degree to which is dependent on the drugs propensity to be absorbed by the substance in those buckets. Is the drug lipophilic (fat loving) or hydrophilic (water loving)?
Each bucket can receive a different amount at differing rates, each bucket can release at differing rate. In other words, the drug has different distributions into each bucket/compartment and their contributions to maintaining equilibrium of drug between the buckets is not equal.
Lipophilic Drugs
If a drug is lipophilic, it is fat loving. It will preferentially accumulate into fat tissue. Muscle has minimal fat stores and so it will only receive a small amount of a lipophilic drug. Initially both the fat and muscle bucket will contribute to maintaining equilibrium with systemic circulation but the muscle bucket will quickly run out of drug. The fat bucket will be the only bucket maintaining equilibrium.
At the time that both muscle and fat have drug to contribute to maintaining equilibrium the volume of distribution will be larger. When muscle runs out of drug and only fat is maintaining equilibrium, the Vd will be smaller. In the multicompartment model, there can be different volumes of distribution that are dependent on the when it is calculated (i.e. time dependent).
If a patient has a significantly higher proportion of body fat, drug may disproportionately accumulate there.
Hydrophilic Drugs
If a drug is hydrophilic, it is water loving. Muscle is approximately 76% water. Fatty tissue only has about 10% water, so it can only receive a small amount of a hydrophilic drug. Initially both fat and muscle buckets will contribute to maintaining equilibrium with systemic circulation but the fat bucket will quickly run out of drug. The muscle bucket will slowly release the drug and after some time will be the only bucket maintaining equilibrium.
Specifically, the loading dose for a drug is calculated using the volume of distribution. Together with the drug’s bioavailability, the dose needed to produce a desired plasma drug concentration can be calculated from the volume of distribution.
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What Can Affect Body Fluid Distribution
Again, at a point, muscle and fat will be contributing to equilibrium and as time moves on, only muscle will. This is why we can have multiple, time dependent volumes of distribution that can be calculated with the multicompartment model.
When a patient has severe burns, the capillaries become more permeable. Fluid moves from the intravascular space into the extravascular spaces. A lipophilic drug, under these circumstances, would concentrate in places it was never intended to.
Heart failure is another condition where the patient could become fluid overloaded, again changing the body’s fluid composition. Third spacing and dehydration are 2 other medical conditions that can alter body composition.
Calculating Multiple Vd in Multicompartment Models
We’ve already discussed why drugs that follow the multicompartment model can have different volumes of distribution. If we check drug plasma concentration when all the compartments are contributing to equilibrium, the Vd might look different than when we check 6 hours later and the muscle bucket has released all its stores while the “fat bucket” still has drug.
Multicompartment volume of distribution can be calculated using the same equation as the single compartment model but all the components of the equation (drug amount and plasma concentration) has to be at a specified time. The drug amount at a specific time can be estimated via elimination constants.
Clinical Significance of Vd
Drugs exist in the body continuously flowing between the intravascular and extravascular space. Only drug in the intravascular space is available for metabolism and elimination from the body. As drug in the intravascular space is metabolized and eliminated, equilibrium is restored between the 2 spaces by movement of the drug from the extravascular space into systemic circulation.
This equilibrium-elimination cycle will continue until all drug is cleared after a single dose or it will continue as long as there is repeated dosing. The equilibrium – elimination cycle of the distribution phase is therefore significant in the determination of the dosing regimen for a drug.
Calculating Loading Dose
Once the loading dose is determined, the rate of clearance will determine how quickly the drug will move from the body compartments to systemic circulation for metabolism and elimination. The rate of clearance will therefore determine the frequency of dosing required to maintain a target blood concentration of the drug.
The role of protein binding and drug transport will be addressed in another study unit. This is where the acidic and basic properties of a drug come into play. This is another factor that can affect the volume of distribution of a drug. It will be better addressed in its own study unit.
Understanding volume of distribution is more than about the calculation of a value. It allows you to visualize the continuous back and forth that occurs in the body when a patient receives a medication and how sensitive that balance is to changes in body composition.
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