Volume of distribution

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The volume of distribution (VD), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Therefore, if VD is greater, it shows that the drug is more diluted than it should be (in the blood plasma), meaning more of it is distributed in tissue (i.e. not in plasma). It is defined as the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing. It is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.[1][2] In rough terms, drugs with high lipid solubility (non-polar), low rates of ionization or low plasma binding capabilities have higher volumes of distribution than drugs which are more polar, more highly ionized or exhibit high plasma binding in the body's environment.

Volume of distribution may be increased by renal 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.

Equations[edit]

The volume of distribution is given by the following equation:

{V_{D}} = \frac{\mathrm{total \ amount \ of \ drug \ in \ the \ body}}{\mathrm{drug \ blood \ plasma \ concentration}}

Therefore the dose required to give a certain plasma concentration can be determined if the VD for that drug is known. The VD is not a physiologic 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 units for Volume of Distribution are typically reported in (ml or liter)/kg body weight. The fact that VD is a ratio of a theoretical volume to a fixed unit of body weight explains why the VD for children is typically higher than that for adults, even though children are smaller and weigh less. As body composition changes with age, VD decreases.

The VD may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood:

{V_{D}} = {V_{P}} + {V_{T}} \left(\frac{fu}{fu_{t}}\right)

Where:

  • VP = plasma volume
  • VT = apparent tissue volume
  • fu = fraction unbound in plasma
  • fuT = fraction unbound in tissue

Examples[edit]

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 C_0 which directly corresponds to the amount of blood contained in the body V_{blood}. Mathematically this would be:

C_0 = D/V_{blood}

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 V_D quantifies just that by specifying how big a volume you would need in order to observe the blood concentration actually measured.

A practical 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 V_{blood}=0.08 l/kg .[3] This gives a C_0=100 µg/ml if the drug stays in the blood stream only, and thus its volume of distribution is the same as V_{blood} that is V_D= 0.08 l/kg. If the drug distributes into all body water the volume of distribution would increase to approximately V_D=0.57 l/kg [4]

If the drug readily diffuses into the body fat the volume of distribution may increase dramatically, an example is chloroquine which has a V_D=250-302 l/kg [5]

In the simple mono-compartmental case the volume of distribution is defined as: V_D=D/C_0, where the C_0 in practice is an extrapolated concentration at time=0 from the first early plasma concentrations after an IV-bolus administration (generally taken around 5min - 30min after giving the drug).

Drug VD Comments
Warfarin 8L Reflects a high degree of plasma protein binding.
Theophylline, Ethanol 30L Represents distribution in total body water.
Chloroquine 15000L Shows highly lipophilic molecules which sequester into total body fat.
NXY-059 8L Highly charged hydrophilic molecule.

Sample values and equations[edit]

Characteristic Description Example value Symbol Formula
Dose Amount of drug administered. 500 mg D Design parameter
Dosing interval Time between drug dose administrations. 24 h \tau Design parameter
Cmax The peak plasma concentration of a drug after administration. 60.9 mg/L C_\text{max} Direct measurement
tmax Time to reach Cmax. 3.9 h t_\text{max} Direct measurement
Cmin The lowest (trough) concentration that a drug reaches before the next dose is administered. 27.7 mg/L C_{\text{min}, \text{ss}} Direct measurement
Volume of distribution The apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration to drug amount in the body). 6.0 L V_\text{d} = \frac{D}{C_0}
Concentration Amount of drug in a given volume of plasma. 83.3 mg/L C_{0}, C_\text{ss} = \frac{D}{V_\text{d}}
Elimination half-life The time required for the concentration of the drug to reach half of its original value. 12 h t_\frac{1}{2} = \frac{ln(2)}{k_\text{e}}
Elimination rate constant The rate at which a drug is removed from the body. 0.0578 h−1 k_\text{e} = \frac{ln(2)}{t_\frac{1}{2}} = \frac{CL}{V_\text{d}}
Infusion rate Rate of infusion required to balance elimination. 50 mg/h k_\text{in} = C_\text{ss} \cdot CL
Area under the curve The integral of the concentration-time curve (after a single dose or in steady state). 1,320 mg/L·h AUC_{0 - \infty} = \int_{0}^{\infty}C\, \operatorname{d}t
AUC_{\tau, \text{ss}} = \int_{t}^{t + \tau}C\, \operatorname{d}t
Clearance The volume of plasma cleared of the drug per unit time. 0.38 L/h CL = V_\text{d} \cdot k_\text{e} = \frac{D}{AUC}
Bioavailability The systemically available fraction of a drug. 0.8 f = \frac{AUC_\text{po} \cdot D_\text{iv}}{AUC_\text{iv} \cdot D_\text{po}}
Fluctuation Peak trough fluctuation within one dosing interval at steady state 41.8 % %PTF = \frac{C_{\text{max}, \text{ss}} - C_{\text{min}, \text{ss}}}{C_{\text{av}, \text{ss}}} \cdot 100
where
C_{\text{av},\text{ss}} = \frac{1}{\tau}AUC_{\tau, \text{ss}}
[ ]

References[edit]

  1. ^ http://www.merckmanuals.com/professional/sec21/ch324/ch324d.html
  2. ^ "vetmed.vt.edu". 
  3. ^ Alberts, Bruce (2005). "Leukocyte functions and percentage breakdown". Molecular Biology of the Cell. NCBI Bookshelf. Retrieved 2007-04-14. 
  4. ^ Guyton, Arthur C. (1976). Textbook of Medical Physiology (5th ed.). Philadelphia: W.B. Saunders. p. 424. ISBN 0-7216-4393-0. 
  5. ^ Wetsteyn JC (1995). "The pharmacokinetics of three multiple dose regimens of chloroquine: implications for malaria chemoprophylaxis". Br J Clinical Pharmacology 39 (6): 696–9. PMC 1365086. PMID 7654492. 

External links[edit]