# PharmPK Discussion - Volume of Distribution

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• On 5 Jan 2013 at 10:28:12, sahka k (sahka2005.aaa.gmail.com) sent the message
`Dear all,What's the breakpoint to differentiate a certain drug as a low,mediumor high volume of distribution in mice?eg; How would you classify the Vss of a drug in mice if you obtained aVss of 0.027L?Also in a few words what is the main difference between Vz and Vss andwhy 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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• On 5 Jan 2013 at 15:46:32, Rhishikesh Thakare (rhishi24niper.at.gmail.com) sent the message
`Hi Sharz,Volume of distribution (Vd) is proportionality constant which relatesplasma concentration (Cp) to amount of drug in body (Ab) = Ab/ Cp. Inone 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 isfunction of time = Vc (1-e^Kv.t) and one can calculate multiple volumeofdistribution accordingly for example,1) At time zero, Vd is Vc. all molecules are in central compartment.  Vcis used to estimate amount of drug in central compartment at any time.It relates drug in central compartment to concentration in centralcompartment. Vc is not that frequently use in PK. It is useful topredict the initial maximum concentration for i.v. bolus administration(may be in anesthetics) and to anticipate possible side effect whenloading 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. Itcan be used to estimate amount of drug in body at steady state duringmultiple dosing or continuous infusion dosing. It is mostly used Vd. Itis used to calculate the loading dose = Vss*Css/F when immediate orrapid Css is required and drug has long terminal half life.3) At the end of distribution phase, (i.e. when elimination phase isdominant and rate of transfer from tissue back to central compartment issmall) Vd is Varea or Vbeta. It is use to calculate residual amount ofdrugin the body. It is useful in mass balance trial to calculate amountremain to be excreted.Vd of ~ 0.07 L/Kg indicates drug is essentially in plasma, may be watersoluble and largely ionized.Vd of ~ 0.07 - 0.3 L/Kg indicates drug in extracellular fluidsVd of ~ 0.3 - 0.6 L/Kg indicates drug is distributed in total bodyfluidsVd of >  0.6 L/Kg indicates distribution in tissues may have highbinding to peripheral tissuesVolume of distribution is continuous value parameter and there is noexact 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 highThese are approximate values and need to normalize the Vd by body weightfor cross species comparison as allometric exponent is 1 for volume ofdistribution (Although there is exception to this)I hope I answered your questions.Comments from experts are welcome and let me know if there is anycorrection.Thanks and Regards,Rhishikesh ThakareUniversity of Nebraska Medical Center, Omaha, NE, US`
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• On 6 Jan 2013 at 20:47:52, Mahamad Yunnus Mahat (Mahamadyunnusm.at.glenmarkpharma.com) sent the message
`The following message was posted to: PharmPKSaha,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 Vdbased on their experience with PK of several drugs.2. One more way to look into it would be just look at mouse total bodyfluid volume (0.567 L/kg, correct me if am wrong here) and your drugshows a value which is <10% of total body fluid then probably you cancategorize it as low; Vd equal and above total water content can becategorized as high.Yunus`
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• On 7 Jan 2013 at 16:31:55, "Jack G. Shi" (JShi.-at-.incyte.com) sent the message
`The following message was posted to: PharmPKVolume of distribution in pharmacokinetics is a hypothetical value andnot really more than a proportionality constant.  For example, onemeasures the concentration in plasma (Cp) and calculates Vd to be 0.5L/kg, therefore concluded that this drug is not distributed beyond thebody water volume.  Now assume the target of the drug is intracellular,and the drug concentration is measured lower inside these cells (let'ssay 50% of Cp).  Based on the intracellular drug concentration, Vd iscalculated to be 1 L/kg, which supports the statement that this drug isdistributed beyond the body water (~0.6 L/kg).  How can a drug bedistributed both within and beyond the body water volume?  So, thishypothetical parameter all depends on the reference compartment wherethe drug concentration is being measured - in my opinion, Vd is not aphysiological parameter in general senses but too often it is regardedas such.Regards,Jack`
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• On 8 Jan 2013 at 15:46:45, "J.H.Proost" (j.h.proost.at.rug.nl) sent the message
`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, andincreases monotonously from a minimum value of V1 to a maximum value ofVbeta. This does not agree with your equation. Where does this equationcome from? What is Kv?best regards,Hans ProostJohannes H. ProostDept. of Pharmacokinetics, Toxicology and TargetingUniversity Centre for PharmacyAntonius Deusinglaan 19713 AV Groningen, The Netherlands`
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• On 7 Jan 2013 at 16:31:55, "Jack G. Shi" (JShi.-at-.incyte.com) sent the message
`The following message was posted to: PharmPKVolume of distribution in pharmacokinetics is a hypothetical value andnot really more than a proportionality constant.  For example, onemeasures the concentration in plasma (Cp) and calculates Vd to be 0.5L/kg, therefore concluded that this drug is not distributed beyond thebody water volume.  Now assume the target of the drug is intracellular,and the drug concentration is measured lower inside these cells (let'ssay 50% of Cp).  Based on the intracellular drug concentration, Vd iscalculated to be 1 L/kg, which supports the statement that this drug isdistributed beyond the body water (~0.6 L/kg).  How can a drug bedistributed both within and beyond the body water volume?  So, thishypothetical parameter all depends on the reference compartment wherethe drug concentration is being measured - in my opinion, Vd is not aphysiological parameter in general senses but too often it is regardedas such.Regards,Jack[May be a repeat - db]`
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