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The following message was posted to: PharmPK
Dear collegues,
does anyone know how to calculate the
distribution volume of a metabolite of drug? Since it originates from
the drug, the plasma concentration-time curve cannot be fitted by an
exponential equation, even it is possibile to calculate the AUC by
integration. Moreover D(0) is the dose of the drug, from which the
metabolite originates, not the D(0) of the metabolite itself. Is it
possible to, considering the metabolite originated from D(0), use the
formula: D(0)/C(0)=Vd? But how to calculate C(0) with a non-
exponential curve?
Thank you very much.
Sandro Ridone
Sandro Ridone, PharmD, MSc
ENEA-Italian National Agency for New Technologies, Energy and the
Environment
Research Centre of Saluggia
Department of Biotechnologies, Agro-Industry and Health Protection
Radiation Protection Institute
strada per Crescentino, 41
13040 Saluggia (VC)
ITALY
e-mail: sandro.ridone.-at-.enea.it
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Sandro,
The apparent volume of distribution of a metabolite can only be
identified by giving the metabolite into the systemic circulation.
However, if you measure both parent and metabolite after giving the
parent into the systemic circulation it is possible to estimate a
value for the volume if the fraction of parent going to the metabolite
is known or is assumed. It is usually very hard to know this fraction
so it is often assumed to be 1.
The asssumption you make depends on what else you know. The assumption
that the fraction is 1 is similar to your proposal to assume that
D(0)p (the dose of the parent) is the same as D(0)m (the dose of the
metabolite). Because the metabolite is not formed instantly from the
parent the time course of the metabolite will not be a single
exponential so it needs a little bit more effort than extrapolation
back to time zero and solving for Vm=D(0)m/C(0)m.
The time course of parent and metabolite concentrations can be
described by compartmental models. These models can often be expressed
as a system of exponential functions but most modern pharmacokinetic
descriptions use clearance and volume parameterisations and may solve
the system using differential equations. I dont know why you say the
"the plasma concentration-time curve cannot be fitted by an
exponential equation" because this is not true unless the system is
non-linear.
There are many programs available for fitting parent metabolite
pharmacokinetics e.g. Monolix, NONMEM, WinNONlin.
Nick
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-at-.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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<... use the formula: D(0)/C(0)=Vd? But how to calculate C(0) with a
non-exponential curve?>
Sandro: Do you have any evidence that 100%D(0) is transformed to
M(etabolite), thus, M is the SINGLE metabolite formed via D(0)?
Another point to consider is that metabolite(s) kinetics, considering
linear PK at commonly used doses, also follows, or is approximated by,
first-order kinetics.
According to my understanding, if you want to properly proceed, you
have to undertake PK analysis using the synthesized metabolite. Best
regards, Dimiter
--
Dimiter Terziivanov, MD,PhD,DSc,
Professor and Head, Clinic of Clinical Pharmacology and
Pharmacokinetics,
Univ Hosp "St. Ivan Rilski",
15 Acad. Ivan Geshov st, 1431
Sofia,
Bulgaria
e-mail: dterziivanov.-a-.rilski.com; terziiv.-at-.yahoo.com
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<... use the formula: D(0)/C(0)=Vd? But how to calculate C(0) with a
non-exponential curve?>
Sandro: Do you have any evidence that 100%D(0) is transformed to
M(etabolite), thus, M is the SINGLE metabolite formed via D(0)?
Another point to consider is that metabolite(s) kinetics, considering
linear PK at commonly used doses, also follows, or is approximated by,
first-order kinetics.
According to my understanding, if you want to properly proceed, you
have to undertake PK analysis using the synthesized metabolite. Best
regards, Dimiter
--
Dimiter Terziivanov, MD,PhD,DSc,
Professor and Head, Clinic of Clinical Pharmacology and
Pharmacokinetics,
Univ Hosp "St. Ivan Rilski",
15 Acad. Ivan Geshov st, 1431
Sofia,
Bulgaria
e-mail: dterziivanov.aaa.rilski.com; terziiv.at.yahoo.com
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The following message was posted to: PharmPK
Hi Sandro,
As you mentioned, you need to know the amount of the metabolite in
order to estimate its volume. There are two ways to that.
If you have the metabolite, administer it directly. An iv dose of the
metabolite gives you the true volume, while any other route gives you
Vd/F, F being the bioavailability.
The second option requires that you have previous knowledge about the
fraction of your parent drug that is transformed to the metabolite.
Knowing that, it is rather easy to calculate the amount of the
metabolite being produced and hence it distribution volume can be
determined easily.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.at.tgordi.com
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Dear Sandro,
As per my knowledge if you have synthesised metabolite you can easily
calculate your metabolite volume of distribution by administering it
by i.v. route.
Using plasma concentration of metabolite after Parent dosing Vs time
Plot and extrapolation to Yaxis will give you C0.
Hope this will help you,
Regards,
Rahul Vats
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Dear colleagues,
pushing the discussion further, i have a question. is it possible to
calculate the AUC of metabolite then divide it by AUC of parent
compound (after administration of the parent compound) to get the
fraction converted to that metabolite?
Best regards,
Ahmed M. Abdelaziz
Teaching Assistant
GUC
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Ahmed,
The short answer is no. The reason is because the fraction of the
parent converted to the metabolite requires that the clearance of the
metabolite, CLm, is known if you want to use the AUC ratio.
Here are the relevant equations under the simple assumption that the
bioavailability of the parent dose (Dosep) is 1
AUCm=F2m*Dosep/CLm
AUCp=Dosep/CLp
AUCm/AUCp=F2m*Dosep/CLm/(DoseP/CLp) = F2m*CLp/CLm
F2m=AUCm/AUCp*CLm/CLp ; AUCm, AUCp and CLp can be identified but CLm
cannot.
Nick
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Dear Ahmed,
it is possible only when you quantify all possible metabolite and
calculate sum AUC of all metabolite and divide it with Parent AUC then
you will get fraction metabolite conversion.
Regards,
Rahul Vats
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The following message was posted to: PharmPK
Estimating any PK parameters from metabolite data gleaned from a
collection
and bioanalytical method designed for the parent and not for the
metabolite
can lead you and your development program down very lonely roads.
At the very least demonstrate that there are or are no differences in
the
stability/recovery between the parent and metabolite. If there are,
modify
the collection and method to maximize recovery for each or,
alternatively,
develop separate collection and assays for each.
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The following message was posted to: PharmPK
Dear Sandro,
GastroPlus(tm) can calculate the rate of formation of multiple
metabolites,
including metabolites of metabolites, to as many levels as desired. The
ideal way to do this is to have measured Vmax and Km in vitro for
parent and
all metabolites, when the enzymes involved are among those for which
we know
the in vivo expression levels. If you do not have such data, but you
do have
data for the amount of metabolite(s) recovered, then the conversion
rates
might be able to be fitted to match the various kinds of data, including
amount of each species recovered in urine and feces.
The total mass balance is the key to understanding what's happening.
There
are only so many drug molecules, and they have to be somewhere at all
times.
Feel free to contact us if we can be of help.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
Dear collegues,
I would like to thank you for your
indications about V(d) of a metabolite. I had a clearer picture of the
problem after your suggestions.
The case I had to investigate was about a phosphonate salt marked with
Sm-153, so I could follow the clearance of the molecule and also of
the unlabelled radioisotope. I wanted to know the V(d) of free
radioisotope to evaluate liver accumulation.
I decided to solve my problem considering Sm-153 as direct to bone (if
labelled to bone or also unlabelled) and as direct to liver (if
unlabelled). I considered so two differnt storage compartments, but
one V(d), calculated by the radioactivity determined by collecting
blood samples. Radiochromatography allowed me to evaluated the
percentage of unlabelled Sm-153 and its AUC. Considering that in
literature 45% of this circulating chemical species reaches liver I
could calculate its accumulation.
My best regards.
Sandro Ridone
Sandro Ridone, PharmD, MSc
ENEA-Italian National Agency for New Technologies, Energy and the
Environment
Research Centre of Saluggia
Department of Biotechnologies, Agro-Industry and Health Protection
Radiation Protection Institute
strada per Crescentino, 41
13040 Saluggia (VC)
ITALY
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The following message was posted to: PharmPK
Dear collegues,
I would like to thank you for your
indications about V(d) of a metabolite. I had a clearer picture of the
problem after your suggestions.
The case I had to investigate was about a phosphonate salt marked with
Sm-153, so I could follow the clearance of the molecule and also of
the unlabelled radioisotope. I wanted to know the V(d) of free
radioisotope to evaluate liver accumulation.
I decided to solve my problem considering Sm-153 as direct to bone (if
labelled to bone or also unlabelled) and as direct to liver (if
unlabelled). I considered so two differnt storage compartments, but
one V(d), calculated by the radioactivity determined by collecting
blood samples. Radiochromatography allowed me to evaluated the
percentage of unlabelled Sm-153 and its AUC. Considering that in
literature 45% of this circulating chemical species reaches liver I
could calculate its accumulation.
My best regards.
Sandro Ridone
Sandro Ridone, PharmD, MSc
ENEA-Italian National Agency for New Technologies, Energy and the
Environment
Research Centre of Saluggia
Department of Biotechnologies, Agro-Industry and Health Protection
Radiation Protection Institute
strada per Crescentino, 41
13040 Saluggia (VC)
ITALY
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Dear Sandro,
I hate to spoil the party, but I disagree with some of the
interpretations presented in the discussion concerning the Vss/F. To
determine Vss/F you also have to determine the absorption rate
(Perrier&Mayerson, J Pharm Sci. 1982). Actually I don't even agree
with Perrier& Meyerson, except for a very specific case, but that is
another story. In the case of a metabolite, the same rule holds
(formation rate).
Best regards,
Stefan
Prof. Stefan Soback, DVM, PhD, Dip. ECVPT
Director, Food Safety Laboratories
Kimron Veterinary Institute
POBox 12
Beit Dagan 50250
Israel
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