# PharmPK Discussion - Metabolite volume of distribution

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• On 31 Jul 2009 at 16:04:33, Sandro Ridone (bourne5321.-a-.gmail.com) sent the message
`The following message was posted to: PharmPKDear collegues,                           does anyone know how to calculate thedistribution volume of a metabolite of drug? Since it originates fromthe drug, the plasma concentration-time curve cannot be fitted by anexponential equation, even it is possibile to calculate the AUC byintegration. Moreover D(0) is the dose of the drug, from which themetabolite originates, not the D(0) of the metabolite itself. Is itpossible to, considering the metabolite originated from D(0), use theformula: D(0)/C(0)=Vd? But how to calculate C(0) with a non-exponential curve?Thank you very much.           Sandro RidoneSandro Ridone, PharmD, MScENEA-Italian National Agency for New Technologies, Energy and theEnvironmentResearch Centre of SaluggiaDepartment of Biotechnologies, Agro-Industry and Health ProtectionRadiation Protection Institutestrada per Crescentino, 4113040 Saluggia (VC)ITALYe-mail: sandro.ridone.-at-.enea.it`
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• On 1 Aug 2009 at 18:55:48, Nick Holford (bourne5321.at.gmail.com) sent the message
`Sandro,The apparent volume of distribution of a metabolite can only beidentified by giving the metabolite into the systemic circulation.However, if you measure both parent and metabolite after giving theparent into the systemic circulation it is possible to estimate avalue for the volume if the fraction of parent going to the metaboliteis known or is assumed. It is usually very hard to know this fractionso it is often assumed to be 1.The asssumption you make depends on what else you know. The assumptionthat the fraction is 1 is similar to your proposal to assume thatD(0)p (the dose of the parent) is the same as D(0)m (the dose of themetabolite). Because the metabolite is not formed instantly from theparent the time course of the metabolite will not be a singleexponential so it needs a little bit more effort than extrapolationback to time zero and solving for Vm=D(0)m/C(0)m.The time course of parent and metabolite concentrations can bedescribed by compartmental models. These models can often be expressedas a system of exponential functions but most modern pharmacokineticdescriptions use clearance and volume parameterisations and may solvethe system using differential equations. I dont know why you say the"the plasma concentration-time curve cannot be fitted by anexponential equation" because this is not true unless the system isnon-linear.There  are many programs available for fitting parent metabolitepharmacokinetics e.g. Monolix, NONMEM, WinNONlin.Nick--Nick Holford, Professor Clinical PharmacologyDept Pharmacology & Clinical PharmacologyUniversity of Auckland, 85 Park Rd, Private Bag 92019, Auckland, NewZealandn.holford.-at-.auckland.ac.nzhttp://www.fmhs.auckland.ac.nz/sms/pharmacology/holford`
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• On 1 Aug 2009 at 03:29:11, Dimiter Terziivanov (bourne5321.at.gmail.com) sent the message
`<... use the formula: D(0)/C(0)=Vd? But how to calculate C(0) with anon-exponential curve?>Sandro:  Do you have any evidence that 100%D(0) is transformed toM(etabolite), thus, M is the SINGLE metabolite formed via D(0)?Another point to consider is that metabolite(s) kinetics, consideringlinear PK at commonly used doses, also follows, or is approximated by,first-order kinetics.According to my understanding, if you want to properly proceed, youhave to undertake PK analysis using the synthesized metabolite. Bestregards, Dimiter--Dimiter Terziivanov, MD,PhD,DSc,Professor and Head, Clinic of Clinical Pharmacology andPharmacokinetics,Univ Hosp "St. Ivan Rilski",15 Acad. Ivan Geshov st, 1431Sofia,Bulgariae-mail: dterziivanov.-a-.rilski.com; terziiv.-at-.yahoo.com`
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• On 1 Aug 2009 at 03:29:11, Dimiter Terziivanov (bourne5321.aaa.gmail.com) sent the message
`<... use the formula: D(0)/C(0)=Vd? But how to calculate C(0) with anon-exponential curve?>Sandro:  Do you have any evidence that 100%D(0) is transformed toM(etabolite), thus, M is the SINGLE metabolite formed via D(0)?Another point to consider is that metabolite(s) kinetics, consideringlinear PK at commonly used doses, also follows, or is approximated by,first-order kinetics.According to my understanding, if you want to properly proceed, youhave to undertake PK analysis using the synthesized metabolite. Bestregards, Dimiter--Dimiter Terziivanov, MD,PhD,DSc,Professor and Head, Clinic of Clinical Pharmacology andPharmacokinetics,Univ Hosp "St. Ivan Rilski",15 Acad. Ivan Geshov st, 1431Sofia,Bulgariae-mail: dterziivanov.aaa.rilski.com; terziiv.at.yahoo.com`
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• On 1 Aug 2009 at 08:06:05, Toufigh Gordi (bourne5321.aaa.gmail.com) sent the message
`The following message was posted to: PharmPKHi Sandro,As you mentioned, you need to know the amount of the metabolite inorder to estimate its volume. There are two ways to that.If you have the metabolite, administer it directly. An iv dose of themetabolite gives you the true volume, while any other route gives youVd/F, F being the bioavailability.The second option requires that you have previous knowledge about thefraction of your parent drug that is transformed to the metabolite.Knowing that, it is rather easy to calculate the amount of themetabolite being produced and hence it distribution volume can bedetermined easily.ToufighToufigh Gordi, PhDClinical Pharmacology, PK/PD analysis consultantwww.tgordi.comE-mail: tg.at.tgordi.com`
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• On 1 Aug 2009 at 21:02:00, rahul vats (bourne5321.-a-.gmail.com) sent the message
`Dear Sandro,As per my knowledge if you have synthesised metabolite you can easilycalculate your metabolite volume of distribution by administering itby i.v. route.Using plasma concentration of metabolite after Parent dosing Vs timePlot and extrapolation to Yaxis will give you C0.Hope this will help you,Regards,Rahul Vats`
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• On 2 Aug 2009 at 00:50:19, "Ahmed M. Abdelaziz" (bourne5321.-a-.gmail.com) sent the message
`Dear colleagues,pushing the discussion further, i have a question. is it possible tocalculate the AUC of metabolite then divide it by AUC of parentcompound (after administration of the parent compound) to get thefraction converted to that metabolite?Best regards,Ahmed M. AbdelazizTeaching AssistantGUC`
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• On 2 Aug 2009 at 21:34:25, Nick Holford (bourne5321.aaa.gmail.com) sent the message
`Ahmed,The short answer is no. The reason is because the fraction of theparent converted to the metabolite requires that the clearance of themetabolite, CLm, is known if you want to use the AUC ratio.Here are the relevant equations under the simple assumption that thebioavailability of the parent dose (Dosep) is 1AUCm=F2m*Dosep/CLmAUCp=Dosep/CLpAUCm/AUCp=F2m*Dosep/CLm/(DoseP/CLp) = F2m*CLp/CLmF2m=AUCm/AUCp*CLm/CLp ; AUCm, AUCp and CLp can be identified but CLmcannot.Nick`
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• On 2 Aug 2009 at 19:19:01, rahul vats (bourne5321.-at-.gmail.com) sent the message
`Dear Ahmed,it is possible only when you quantify all possible metabolite andcalculate sum AUC of all metabolite and divide it with Parent AUC thenyou will get fraction metabolite conversion.Regards,Rahul Vats`
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• On 2 Aug 2009 at 12:11:28, "Ed O'Connor" (bourne5321.-a-.gmail.com) sent the message
`The following message was posted to: PharmPKEstimating any PK parameters from metabolite data gleaned from acollectionand bioanalytical method designed for the parent and not for themetabolitecan lead you and your development program down very lonely roads.At the very least demonstrate that there are or are no differences inthestability/recovery between the parent and metabolite.  If there are,modifythe collection and method to maximize recovery for each or,alternatively,develop separate collection and assays for each.`
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• On 2 Aug 2009 at 17:07:11, Walt Woltosz (bourne5321.-a-.gmail.com) sent the message
`The following message was posted to: PharmPKDear Sandro,GastroPlus(tm) can calculate the rate of formation of multiplemetabolites,including metabolites of metabolites, to as many levels as desired. Theideal way to do this is to have measured Vmax and Km in vitro forparent andall metabolites, when the enzymes involved are among those for whichwe knowthe in vivo expression levels. If you do not have such data, but youdo havedata for the amount of metabolite(s) recovered, then the conversionratesmight be able to be fitted to match the various kinds of data, includingamount of each species recovered in urine and feces.The total mass balance is the key to understanding what's happening.Thereare only so many drug molecules, and they have to be somewhere at alltimes.Feel free to contact us if we can be of help.Best regards,WaltWalt WoltoszChairman & CEOSimulations Plus, Inc. (NASDAQ: SLP)42505 10th Street WestLancaster, CA  93534-7059U.S.A.http://www.simulations-plus.comE-mail: walt.at.simulations-plus.com`
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• On 5 Aug 2009 at 10:10:07, Sandro Ridone (bourne5321.aaa.gmail.com) sent the message
`The following message was posted to: PharmPKDear collegues,                           I would like to thank you for yourindications about V(d) of a metabolite. I had a clearer picture of theproblem after your suggestions.The case I had to investigate was about a phosphonate salt marked withSm-153, so I could follow the clearance of the molecule and also ofthe unlabelled radioisotope. I wanted to know the V(d) of freeradioisotope to evaluate liver accumulation.I decided to solve my problem considering Sm-153 as direct to bone (iflabelled to bone or also unlabelled) and as direct to liver (ifunlabelled). I considered so two differnt storage compartments, butone V(d), calculated by the radioactivity determined by collectingblood samples. Radiochromatography allowed me to evaluated thepercentage of unlabelled Sm-153 and its AUC. Considering that inliterature 45% of this circulating chemical species reaches liver Icould calculate its accumulation.My best regards.            Sandro RidoneSandro Ridone, PharmD, MScENEA-Italian National Agency for New Technologies, Energy and theEnvironmentResearch Centre of SaluggiaDepartment of Biotechnologies, Agro-Industry and Health ProtectionRadiation Protection Institutestrada per Crescentino, 4113040 Saluggia (VC)ITALY`
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• On 5 Aug 2009 at 10:10:07, Sandro Ridone (bourne5321.-a-.gmail.com) sent the message
`The following message was posted to: PharmPKDear collegues,                           I would like to thank you for yourindications about V(d) of a metabolite. I had a clearer picture of theproblem after your suggestions.The case I had to investigate was about a phosphonate salt marked withSm-153, so I could follow the clearance of the molecule and also ofthe unlabelled radioisotope. I wanted to know the V(d) of freeradioisotope to evaluate liver accumulation.I decided to solve my problem considering Sm-153 as direct to bone (iflabelled to bone or also unlabelled) and as direct to liver (ifunlabelled). I considered so two differnt storage compartments, butone V(d), calculated by the radioactivity determined by collectingblood samples. Radiochromatography allowed me to evaluated thepercentage of unlabelled Sm-153 and its AUC. Considering that inliterature 45% of this circulating chemical species reaches liver Icould calculate its accumulation.My best regards.            Sandro RidoneSandro Ridone, PharmD, MScENEA-Italian National Agency for New Technologies, Energy and theEnvironmentResearch Centre of SaluggiaDepartment of Biotechnologies, Agro-Industry and Health ProtectionRadiation Protection Institutestrada per Crescentino, 4113040 Saluggia (VC)ITALY`
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• On 5 Aug 2009 at 20:42:42, David Bourne (bourne5321.aaa.gmail.com) sent the message
`Dear Sandro,I hate to spoil the party, but I disagree with some of theinterpretations presented in the discussion concerning the Vss/F. Todetermine Vss/F you also have to determine the absorption rate(Perrier&Mayerson, J Pharm Sci. 1982). Actually I don't even agreewith Perrier& Meyerson, except for a very specific case, but that isanother story. In the case of a metabolite, the same rule holds(formation rate).Best regards,StefanProf. Stefan Soback, DVM, PhD, Dip. ECVPTDirector, Food Safety LaboratoriesKimron Veterinary InstitutePOBox 12Beit Dagan 50250Israel`
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