- On 5 Jan 2013 at 10:28:12, sahka k (sahka2005.aaa.gmail.com) sent the message

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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 - On 5 Jan 2013 at 15:46:32, Rhishikesh Thakare (rhishi24niper.at.gmail.com) sent the message

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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 - On 6 Jan 2013 at 20:47:52, Mahamad Yunnus Mahat (Mahamadyunnusm.at.glenmarkpharma.com) sent the message

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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 - On 7 Jan 2013 at 16:31:55, "Jack G. Shi" (JShi.-at-.incyte.com) sent the message

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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 - On 8 Jan 2013 at 15:46:45, "J.H.Proost" (j.h.proost.at.rug.nl) sent the message

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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 - On 7 Jan 2013 at 16:31:55, "Jack G. Shi" (JShi.-at-.incyte.com) sent the message

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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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