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Dear all,
What's the breakpoint to differentiate a certain drug as a low,
medium
or high volume of distribution in mice?
eg; How would you classify the Vss of a drug in mice if you obtained a
Vss of 0.027L?
Also in a few words what is the main difference between Vz and Vss and
why are both calculated, if Vss parameter gives a more accurate interpretation.
Your expert advice would be much appreciated.
Many thanks,
Sharz
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Hi Sharz,
Volume of distribution (Vd) is proportionality constant which relates
plasma concentration (Cp) to amount of drug in body (Ab) = Ab/ Cp. In
one compartment PK the above ratio is constant and hence only one Vd.
However, in multi-compartmental PK Ab and Cp is not constant and Vd is
function of time = Vc (1-e^Kv.t) and one can calculate multiple volume
of
distribution accordingly for example,
1) At time zero, Vd is Vc. all molecules are in central compartment. Vc
is used to estimate amount of drug in central compartment at any time.
It relates drug in central compartment to concentration in central
compartment. Vc is not that frequently use in PK. It is useful to
predict the initial maximum concentration for i.v. bolus administration
(may be in anesthetics) and to anticipate possible side effect when
loading dose in rapidly administered (Cmax)
2) At equilibrium, (i.e. rate of change in tissue concentration is zero)
Vd is Vss. It relates amount of drug in body to Cp at equilibrium. It
can be used to estimate amount of drug in body at steady state during
multiple dosing or continuous infusion dosing. It is mostly used Vd. It
is used to calculate the loading dose = Vss*Css/F when immediate or
rapid Css is required and drug has long terminal half life.
3) At the end of distribution phase, (i.e. when elimination phase is
dominant and rate of transfer from tissue back to central compartment is
small) Vd is Varea or Vbeta. It is use to calculate residual amount of
drug
in the body. It is useful in mass balance trial to calculate amount
remain to be excreted.
Vd of ~ 0.07 L/Kg indicates drug is essentially in plasma, may be water
soluble and largely ionized.
Vd of ~ 0.07 - 0.3 L/Kg indicates drug in extracellular fluids
Vd of ~ 0.3 - 0.6 L/Kg indicates drug is distributed in total body
fluids
Vd of > 0.6 L/Kg indicates distribution in tissues may have high
binding to peripheral tissues
Volume of distribution is continuous value parameter and there is no
exact break points. However, general notion is 0.07 - 0.6 L/kg is low,
0.6 - 5 L/kg moderate and > 5 L/kg is high
These are approximate values and need to normalize the Vd by body weight
for cross species comparison as allometric exponent is 1 for volume of
distribution (Although there is exception to this)
I hope I answered your questions.
Comments from experts are welcome and let me know if there is any
correction.
Thanks and Regards,
Rhishikesh Thakare
University of Nebraska Medical Center, Omaha, NE, US
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The following message was posted to: PharmPK
Saha,
Two possibilities.
1. Lee Di text book categorize Vd in to high and low in rodents
(<1L/kg-Low: >10L/kg-High). Here probably authors have categorized Vd
based on their experience with PK of several drugs.
2. One more way to look into it would be just look at mouse total body
fluid volume (0.567 L/kg, correct me if am wrong here) and your drug
shows a value which is <10% of total body fluid then probably you can
categorize it as low; Vd equal and above total water content can be
categorized as high.
Yunus
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The following message was posted to: PharmPK
Volume of distribution in pharmacokinetics is a hypothetical value and
not really more than a proportionality constant. For example, one
measures the concentration in plasma (Cp) and calculates Vd to be 0.5
L/kg, therefore concluded that this drug is not distributed beyond the
body water volume. Now assume the target of the drug is intracellular,
and the drug concentration is measured lower inside these cells (let's
say 50% of Cp). Based on the intracellular drug concentration, Vd is
calculated to be 1 L/kg, which supports the statement that this drug is
distributed beyond the body water (~0.6 L/kg). How can a drug be
distributed both within and beyond the body water volume? So, this
hypothetical parameter all depends on the reference compartment where
the drug concentration is being measured - in my opinion, Vd is not a
physiological parameter in general senses but too often it is regarded
as such.
Regards,
Jack
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Dear Rhishikesh,
In reply to Sharz you wrote:
> However, in multi-compartmental PK Ab and Cp is not constant and
> Vd is function of time = Vc (1-e^Kv.t) and one can calculate multiple
> volume of distribution accordingly for example
>
I don't think this equation is correct. Indeed, Vd is not constant, and
increases monotonously from a minimum value of V1 to a maximum value of
Vbeta. This does not agree with your equation. Where does this equation
come from? What is Kv?
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
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The following message was posted to: PharmPK
Volume of distribution in pharmacokinetics is a hypothetical value and
not really more than a proportionality constant. For example, one
measures the concentration in plasma (Cp) and calculates Vd to be 0.5
L/kg, therefore concluded that this drug is not distributed beyond the
body water volume. Now assume the target of the drug is intracellular,
and the drug concentration is measured lower inside these cells (let's
say 50% of Cp). Based on the intracellular drug concentration, Vd is
calculated to be 1 L/kg, which supports the statement that this drug is
distributed beyond the body water (~0.6 L/kg). How can a drug be
distributed both within and beyond the body water volume? So, this
hypothetical parameter all depends on the reference compartment where
the drug concentration is being measured - in my opinion, Vd is not a
physiological parameter in general senses but too often it is regarded
as such.
Regards,
Jack
[May be a repeat - db]
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