Volume of distribution

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The volume of distribution (V_D), 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

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 V_D for that drug is known. The V_D 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 V_D is a ratio of a theoretical volume to a fixed unit of body weight explains why the V_D for children is typically higher than that for adults, even though children are smaller and weigh less. 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:

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

Where:

V_P = plasma volume

V_T = apparent tissue volume

fu = fraction unbound in plasma

fu_T = fraction unbound in tissue

Examples

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 $C_{0}$ 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	V_D	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

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
C_max	The peak plasma concentration of a drug after administration.	60.9 mg/L	$C_{{\text{max}}}$	Direct measurement
t_max	Time to reach C_max.	3.9 h	$t_{{\text{max}}}$	Direct measurement
C_min	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	$AUC_{{0-\infty }}$	$=\int _{{0}}^{{\infty }}C\,\operatorname {d}t$
Area under the curve		1,320 mg/L·h	$AUC_{{\tau ,{\text{ss}}}}$	$=\int _{{t}}^{{t+\tau }}C\,\operatorname {d}t$
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

↑ http://www.merckmanuals.com/professional/sec21/ch324/ch324d.html
↑ "vetmed.vt.edu".
↑ Alberts, Bruce (2005). "Leukocyte functions and percentage breakdown". Molecular Biology of the Cell. NCBI Bookshelf. Retrieved 2007-04-14.
↑ Guyton, Arthur C. (1976). Textbook of Medical Physiology (5th ed.). Philadelphia: W.B. Saunders. p. 424. ISBN 0-7216-4393-0.
↑ 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

v t e Concepts in Pharmacology

Pharmacokinetics	ADME: Absorption Distribution Metabolism Excretion (Clearance) Loading dose Volume of distribution (Initial) Rate of infusion Compartment Bioequivalence Bioavailability Onset of action Biological half-life Plasma protein binding Therapeutic index (LD₅₀/ED₅₀)

Pharmacodynamics	Toxicity (Neurotoxicology) Dose–response relationship (Efficacy, Potency) Antimicrobial pharmacodynamics: Minimum inhibitory concentration/Bacteriostatic Minimum bactericidal concentration/Bactericide

Agonism and antagonism	Agonist: Inverse agonist Irreversible agonist Partial agonist Superagonist Physiological agonist Antagonist: Competitive antagonist Irreversible antagonist Physiological antagonist Other: Binding Affinity Binding selectivity Functional selectivity

Other	Drug tolerance: Tachyphylaxis Drug resistance: Antibiotic resistance Multiple drug resistance

Drug discovery strategies	Classical pharmacology Reverse pharmacology

Related fields/subfields	Pharmacogenetics Pharmacogenomics Neuropsychopharmacology (Neuropharmacology, Psychopharmacology)

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