# PharmPK Discussion - Correlation between dose and clearance

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• On 27 Oct 2009 at 17:31:09, Neha Bhandari (Neha_Bhandari.-a-.jubl.com) sent the message
`The following message was posted to: PharmPKDear All,Is there any generalized correlation for Dose and clearance ?Or Can Clearance be calculated for varying doses (amount of drug inthe body) (Either Oral or IV) ?Thanks & Regards,Neha Bhandari`
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• On 28 Oct 2009 at 07:41:16, Nick Holford (n.holford.-a-.auckland.ac.nz) sent the message
`Neha,You asked: > Is there any generalized correlation for Dose and clearance ?The first fundamental relation in pharmacokinetics is:Rate Out = Clearance x  ConcentrationAt steady state this means:Rate In = Clearance x ConcentrationIf you replace the Rate In by the maintenance dose rate i.e. the "dose":Maintenance Dose Rate =  Clearance x ConcentrationThis shows the answer to your first question. The "correlation"between dose and clearance is 100%. Indeed you can think of clearanceas the factor that "correlates" dose and concentration.It also shows the answer to your second question. Clearance can alwaysbe calculated from the dose rate and the steady state concentration.There are very well known methods for calculating clearance from non-steady state concentrations described in pharmacokinetic textbooks. Innearly all cases clearance is a constant for a particular drug so youonly need to study concentrations after one dose to calculate theclearance (see below for more details).With regard to your second question: > Or Can Clearance be calculated for varying doses (amount of drug inthe body) (Either Oral or IV) ?The amount in the body is only equal to the dose at the instant thedose is given -- after that the amount will decrease (due toelimination by a clearance process).The second fundamental relation in pharmacokinetics is:Amount in Body = Volume of Distribution x ConcentrationSee these links for more details about the basic ideas about clearanceand volume of distribution and some of the more complicated issuessuch as capacity limited elimination when clearance will changedepending on the dose:http://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/clearance_ppt.pdfhttp://www.fmhs.auckland.ac.nz/faculty/teaching/mbchb209/_docs/volume_of_distribution_ppt.pdfNick--Nick Holford, Professor Clinical PharmacologyDept Pharmacology & Clinical PharmacologyUniversity of Auckland, 85 Park Rd, Private Bag 92019, Auckland, NewZealandn.holford.-a-.auckland.ac.nz`
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• On 27 Oct 2009 at 13:51:22, "Walt Woltosz" (walt.-at-.simulations-plus.com) sent the message
`The following message was posted to: PharmPKNeha,Just to add a bit to Nick Holford's post - recognize that when he says"dose" or "dose rate" it refers to the amount of drug that reaches thesystemic circulation. If bioavailability is 100%, then it's the sameas theadministered dose. If not, you need to reduce it to the amount that wasbioavailable.Best regards,Walt WoltoszChairman & CEOSimulations Plus, Inc. (NASDAQ: SLP)42505 10th Street WestLancaster, CA  93534-7059U.S.A.http://www.simulations-plus.com`
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• On 28 Oct 2009 at 13:35:29, "Doogue, Matt (Health)" (Matt.Doogue.aaa.health.sa.gov.au) sent the message
`The following message was posted to: PharmPKNehaAnd a further point to consider, after those mentioned by Nick andWalt is saturable elimination.  Phenytoin being a teaching examplewith saturable metabolism.CheersMattDr Matt DoogueClinical Pharmacologist / EndocrinologistFlinders Medical Centre, Flinders University`
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• On 28 Oct 2009 at 14:40:25, "Ravi Sankar Prasad Talluri [5336]" (ravisankar.t.-a-.saiadvantium.com) sent the message
`The following message was posted to: PharmPKHello,If the rate of elimination follows the first order (drug is eliminatedby non saturable processes), Clearance shouldn't change (constant fora drug) with the increase/decrease in the dose.However, I have encountered drugs more with mixed order kinetics(first order elimination at lower doses and zero (pseudo zero) orderat higher doses). This is due to the involvement of saturableprocesses (metabolizing enzymes or transporters) in the elimination ofthe drug.In these cases you could find a decrease in clearance with dose. MMkinetics would be helpful to describe this phenomenon.As an example you can look at Itricanazole pK in rats...ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2004, p. 1756 - 1762 by JeeH Shin et al.In fact looking at clearance at escalating doses will allow us todelineate whether the drug get eliminated by any non-linear pathways.Hope this would be helpful.ThanksRavi Talluri Ph.DSai Advantium Pharma, Pune`
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• On 29 Oct 2009 at 10:40:25, veeravalli vijay bhaskar (veeravalli.bhaskar.-at-.gmail.com) sent the message
`Hello,      In non compartmental analysis clearance can be calculated byusing the following equation         clearance =dose/AUC.In case of IV dosing the dose can be taken as such (100 %bioavailable). but for oral dosing the clearance is calculated basedon fraction of dose absorbed.With regards,V. Vijaya Bhaskar`
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