I have an orally administered drug which is given daily. The parent isBack to the Top
extensively metabolized and has low bioavailability. There are a few
major metabolites that have been quantified in plasma.
After a single dose, metabolite exposure is
AUC Metabolite 1 = AUC Metabolite 2 > AUC Metabolite 3 = 25% of
Metabolite 1
AUCs of metabolites >> AUC of parent.
After one month dosing of daily dosing, the levels of the metabolites
significantly change in this manner:
Metabolite 1 with half-life of 3 hours: AUC, Cmaxdecrease by 50%
Metabolite 2 with half-life of 3 hours: AUC, Cmax decrease by 50%
Metabolite 3 with half-life of 5 hours: AUC, Cmax increase 2to 3x
With repeat dosing AUC metab 3 is now 2x that of metab 1.
What'sgoing on?
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Do you know the enzymes involved in each route?
A possibility: maybe the enzyme(s) responsible for metabolites 1 and 2
formation was inhibited by parent or one of the metabolites or
something present on the formulation and then there were more parent
free to form metabolite 3, which route has not been affected. ?!
Another possibility: maybe the enzyme(s) responsible for metabolite 3
is induced and there are less parent to form metabolites 1 and 2. ?!
Of course these are only two possibilities, there must be others. It is
very important to know the enzymes involved to finally conclude.
Hope it had helped,
Paula Macedo Cerqueira, PhD
S\0x201Eo Paulo- Brazil
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First thought,
Is there any chance that metabolites 1 and 2 are further converted to
metabolite 3 and that this pathway is inducible upon chronic drug
treatment? It is difficult to tell if this is feasible without
seeing the mass balance for the metabolites.
All the very best,
Bernard
Bernard Murray, Ph.D.
Senior Research Investigator
Drug Metabolism, PCS, PPD, GPRD, Abbott Laboratories, Chicago, USA
Bernard.Murray.-at-.abbott.com
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Dr. Stapleton,
Your metabolite 1 may be giving rise to metabolite 3 in a sequential
manner.
The enzyme that is responsible for catalyzing conversion of metabolite
1 to
3 (eg. CYP3A4) may be inducible by your parent (or by metabolite 1
itself.)
This phenomenon is called auto-induction of clearance eg. Carbamazepine.
If the metabolism is not sequential, induction of metabolite 3 pathway
will
still explain increase in its AUC, but will not explain decrease in 1
and 2.
In this case, there may be a prefential metabolism of parent to
metabolite 3 going on.
Rucha Sane
Graduate Student
University of Cincinnati.
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I agree, but think the last if the most probable. Harold
Back to the Top
Dear Mr.Stapleton,
Your observations are very interesting. Now, before going for any
further studies its better to characterize the metabolites. Once
characterization is done, one important point that can be clarified is
whether once metabolite is acting as a parent for the generation of
other. It appears from the observations that such a phenomenon is
existing.
Assuming the case that metabolite 1 and/or metabolite 2 are acting as
parent(s) for the generation of metabolite 3 one possible explanation
is as follows.
On repeated dosing, parent compound may be inducing the cytochrome
P450's responsible for generation of metabolite 1 and 2, which is
finally resulting in the accumulation of metabolite 3
Another possible explanation is along with the induction as mentioned
in the first case, parent molecule may be inhibiting the PhaseII
metabolism of metabolite 3, which is resulting in the accumulation of
metabiolite3.
Regards,
Ravi Kanth Bhamidipati
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Mikey,
I not sure if this was a question from your side:
"AUCs of metabolites >> AUC of parent."
but will make a comment on that. Metabolite concentrations (and thereby
AUCs) might be larger than the parent compound due to smaller volume of
distribution, which could be due to the metabolites being less
lipophilic.
I believe you have received very credible answers from others with
regard to the changes in metabolite AUCs upon repeated administrations.
However, it would be nice to know whether the AUC of the parent
compound changes over time as well. This might shed a light on whether
metabolite 3 is formed from the parent compound or is a secondary
metabolite, as proposed in an earlier response. Also, what is the
half-life of the parent compound?
Toufigh Gordi, PhD
Thanks to all for the interesting and helpful responses.Back to the Top
Toufigh:
AUC of parent does not change over time, but the shape of the PK
profile does: Tmax{parent} following initial dose is at 4 hrs,
Tmax{parent} after repeat dosing is about 1 hour.
Tmax for each:
Parent: Initial=4 hrs, Repeat => 1 hr
Metab 1: Initial=1 hr , Repeat => no change
Metab 2: Initial=1 hr, Repeat => no change
Metab 3: Initial=1 hr, Repeat => 2 hrs
The half-life of parent is similar to that of metabolite 3, i.e. 5 hrs.
Thanks.
KS
Mr.Stapleton,Back to the Top
Has the Cmax of the parent changed after repeated doses, or only the
tmax?
What about the metabolites t1/2? If their half life has not changed, I
wouldn't believe that the metabolites elimination is reduced.
Do you know the CYPs involved in each process? Again, after so many
possibilities, this information will help to conduct to the most
possible one.
Paula Macedo Cerqueira, PhD
S\0x201Eo Paulo- Brazil
TG:Back to the Top
Concentrations of parent tended to be quite low. Metabolites account
fora majorityof exposure. Because of the sample collection time
scheme and the relatively late Tmax for parenton day 1,half-life of
parent could only be estimatedfor the profile of the later PK
assessment day (i.e. after repeat dosing). There may be some more
complex (more convoluted as opposed to the day 1 profile?) processes
going on at that point, but the eliminationphase of the curve was
fairly well defined and consequently thehalf-life estimates appear
reliable.
I think that parent is metabolized rapidly and extent of metabolism is
correlated with expression of P450 3A.
We have PK on parent from IV, but none onmetabolites.
KS
Hi!Back to the Top
You have provided the following information in your past mails:
"Metabolite 1 with half-life of 3 hours: AUC, Cmaxdecrease by 50%
Metabolite 2 with half-life of 3 hours: AUC, Cmax decrease by 50%
Metabolite 3 with half-life of 5 hours: AUC, Cmax increase 2to 3x"
and
"The half-life of parent is similar to that of metabolite 3, i.e. 5
hrs."
Half-life estimates of a metabolite, if generated after the
administration of the parent drug, might not reflect the true half-life
of the metabolite. Metabolites with a shorter half-lives than the
parent compound will show values similar to the half-life of the parent
compound, since their elimination is rate-limited by their production.
However, I believe that in a certain circumstance this could happen:
the parent compound is given orally and is metabolized very rapidly
during the first pass over liver so that a lot of metabolite is built
before it starts to be eliminated. Do you think your parent drug is
such a compound ?
It is difficult to evaluate your situation more without taking a look
at how different PK parameters were generated and what the quality of
the underlying data was. Do you have any iv data on the drug and its
metabolites after single or repeated iv doses?
Toufigh
(Note: A metabolite may have shorter half-life than the parent drug. To
estimate the true half-life of the metabolite, one needs to administer
the metabolite intravenously and estimate the PK parameters. If the PK
of the metabolite is studied in conjunction with the parent drug, one
needs to be cautious about the observed PK parameters for the
metabolite, since the elimination of the metabolite might be rate
limited by its production rate)
Dear Mr.Stapleton,Back to the Top
I have been reading all these interesting remarks from the forum
concerning
your observations, but surprisingly most of them are pointing out the
idea
of metabolite 1/2 acting as parent for the subsequent generation of
metabolite 3. Obviously, this is a quite possible explanation requiring
further experimental evidences to support it. However, I would like to
pose
another way. What about the possible saturation of both metabolite1/2
routes
after repeated doses that can then switch parent metabolism into the
alternative metabolite 3 route (lower affinity, higher capacity in
relation
to those for metabolite 1/2 formation)?. I think it would be a real
possibility that could not be discarded.
I hope this help.
Jorge Duconge
Dear all,Back to the Top
What Dr. Duconge suggested would explain increase in M3. However, why
will
it reduce formation of M1 and M2?
Also, about the halflives of metabolites: have they been calculated
from the
elimination phases after the dosing was terminated? Or back calculated
from
time to reach steady state? The later will give erroneous results if
enzyme
induction is involved.
Metabolite PK is either formation dependent or elimination dependent and
that will govern the half life.
sorry to be adding more factors here but what about protein binding of
these
metabolites? Could M2 and M1 be displacing M3 from tissue/plasma
proteins?
just curious.
Regards,
Rucha.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)