In pharmacology, the volume of distribution (V_{D}, also known as apparent volume of distribution, literally, volume of dilution^{[1]}) is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.^{[2]} In other words, it is the ratio of amount of drug in a body (dose) to concentration of the drug that is measured in blood, plasma, and un-bound in interstitial fluid.^{[3]}^{[4]}
The V_{D} of a drug represents the degree to which a drug is distributed in body tissue rather than the plasma. V_{D} is directly proportional with the amount of drug distributed into tissue; a higher V_{D} indicates a greater amount of tissue distribution. A V_{D} greater than the total volume of body water (approximately 42 liters in humans^{[5]}) is possible, and would indicate that the drug is highly distributed into tissue. In other words, the volume of distribution is smaller in the drug staying in the plasma than that of a drug that is widely distributed in tissues.^{[6]}
In rough terms, drugs with a high lipid solubility (non-polar drugs), low rates of ionization, or low plasma protein binding capabilities have higher volumes of distribution than drugs which are more polar, more highly ionized or exhibit high plasma protein binding in the body's environment. Volume of distribution may be increased by kidney failure (due to fluid retention) and liver failure (due to altered body fluid and plasma protein binding). Conversely it may be decreased in dehydration.
The initial volume of distribution describes blood concentrations prior to attaining the apparent volume of distribution and uses the same formula.
The volume of distribution is given by the following equation:
Therefore, the dose required to give a certain plasma concentration can be determined if the V_{D} for that drug is known. The V_{D} is not a physiological value; it is more a reflection of how a drug will distribute throughout the body depending on several physicochemical properties, e.g. solubility, charge, size, etc.
The unit for Volume of Distribution is typically reported in litres. As body composition changes with age, V_{D} decreases.
The V_{D} may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood:
Where:
Main article: Table of volume of distribution for drugs |
If you administer a dose D of a drug intravenously in one go (IV-bolus), you would naturally expect it to have an immediate blood concentration which directly corresponds to the amount of blood contained in the body . Mathematically this would be:
But this is generally not what happens. Instead you observe that the drug has distributed out into some other volume (read organs/tissue). So probably the first question you want to ask is: how much of the drug is no longer in the blood stream? The volume of distribution quantifies just that by specifying how big a volume you would need in order to observe the blood concentration actually measured.
An example for a simple case (mono-compartmental) would be to administer D=8 mg/kg to a human. A human has a blood volume of around 0.08 L/kg .^{[7]} This gives a 100 µg/mL if the drug stays in the blood stream only, and thus its volume of distribution is the same as that is 0.08 L/kg. If the drug distributes into all body water the volume of distribution would increase to approximately 0.57 L/kg ^{[8]}
If the drug readily diffuses into the body fat the volume of distribution may increase dramatically, an example is chloroquine which has a 250-302 L/kg ^{[9]}
In the simple mono-compartmental case the volume of distribution is defined as: , where the in practice is an extrapolated concentration at time = 0 from the first early plasma concentrations after an IV-bolus administration (generally taken around 5 min - 30 min after giving the drug).
Drug | V_{D} | Comments |
Warfarin | 8 L | Reflects a high degree of plasma protein binding. |
Theophylline, Ethanol | 30 L | Represents distribution in total body water. |
Chloroquine | 15000 L | Shows highly lipophilic molecules which sequester into total body fat. |
NXY-059 | 8 L | Highly charged hydrophilic molecule. |
Characteristic | Description | Symbol | Unit | Formula | Worked example value |
---|---|---|---|---|---|
Dose | Amount of drug administered. | Design parameter | 500 mmol | ||
Dosing interval | Time between drug dose administrations. | Design parameter | 24 h | ||
C_{max} | The peak plasma concentration of a drug after administration. | Direct measurement | 60.9 mmol/L | ||
t_{max} | Time to reach C_{max}. | Direct measurement | 3.9 h | ||
C_{min} | The lowest (trough) concentration that a drug reaches before the next dose is administered. | Direct measurement | 27.7 mmol/L | ||
C_{avg} | The average plasma concentration of a drug over the dosing interval in steady state. | 55.0 h×mmol/L | |||
Volume of distribution | The apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration in plasma to drug amount in the body). | 6.0 L | |||
Concentration | Amount of drug in a given volume of plasma. | 83.3 mmol/L | |||
Absorption half-life | The time required for 50% of a given dose of drug to be absorbed into the systemic circulation.[1] | 1.0 h | |||
Absorption rate constant | The rate at which a drug enters into the body for oral and other extravascular routes. | 0.693 h^{−1} | |||
Elimination half-life | The time required for the concentration of the drug to reach half of its original value. | 12 h | |||
Elimination rate constant | The rate at which a drug is removed from the body. | 0.0578 h^{−1} | |||
Infusion rate | Rate of infusion required to balance elimination. | 50 mmol/h | |||
Area under the curve | The integral of the concentration-time curve (after a single dose or in steady state). | 1,320 h×mmol/L | |||
Clearance | The volume of plasma cleared of the drug per unit time. | 0.38 L/h | |||
Bioavailability | The systemically available fraction of a drug. | Unitless | 0.8 | ||
Fluctuation | Peak–trough fluctuation within one dosing interval at steady state. |
where |
41.8% |