Hello,Back to the Top
I have a question related to the possibility to using AUC of metabolite
(as compared to AUC of parent drug) to assess oral availability of the
parent.
In rodents the parent compound is quickly metabolised and gives a
metabolite that has CL much slower than the parent with a much larger
AUC. Assessing parent gives large variability of cmax and AUC between
animals, but the metabolite much less variability is seen with both AUC
and Cmax. If I assume similar amount of metabolism to this metablite,
can I use AUC of the metabolite to compare relative availability of
parent drug formulations?
Any comments and references on this matter would be most welcomed.
P.S. This parent drug is not to be considered for this issue as a
prodrug.
Thanks
Ernesto
Ernesto:Back to the Top
I don't think you can.
Liver first-pass metabolism is a major contributor to poor oral
bioavailability. Even if you have a higher metabolite AUC, that does
not mean the drug has been absorbed in an intact form from the GI tract
into the systemic circulation. In other words, a higher metabolite AUC
doesn't correlate with a higher bioavailability.
D.
Dear Song DiBack to the Top
Regarding Ernesto's question and while I agree with your caution in
interpreting the results, I don't see why you cannot regard the
(significantly) higher main metabolite AUC as an indication that the
formulation might be more available......provided always that it was
done under properly controlled conditions in a balanced design. Indeed,
if the conditions are so controlled, what would be your alternative
explanations? It might be possible to double or quadruple the dose of
one form or to deliberately introduce a formulation...say delayed
release of some kind, to give some clues to the relationship between
formulation and metabolite AUC. I would be against refusing to do any
study at all as it sounds like throwing the baby out with the
bathwater, pragmatically speaking.
Kind regards
Andrew Sutton
http://www.science.uwa.edu.au/for/postgrad/masters/pharmacy
[I was involved in a bioavailability study for a spironolactone(?)
product and we analyzed metabolites concentration after a week of
dosing, seemed reasonable and useful at the time - db]
Dear Andrew,Back to the Top
Considering the definition of bioavailability (BA) - "availability of
intact drug to systemic circulation" - assessing the drug's BA using
metabolite AUC may not seem appropriate (especially if metabolism is pre-systemic). However, I hope, one can use metabolite AUC to estimate parent exposure if metabolism is post-systemic.
Also it is difficult to predict the rate of absorption of parent based
on metabolite formation rate. For example if two formulations have
different rates of dissolution leading to differential absorption rates might
lead to differential parent concentrations at the transporter (if any involved)
or enzyme site. If the transport or metabolic processes are saturable in
one case and not in other case, that might lead to different parent or
metabolite profiles. So, keeping in mind of these complex processes its
not ideal to predict parent exposure based on metabolite AUC.
However, ratio of parent to metabolite could be an useful parameter to
depend on in these kind of situations.
Any comments on my views on this subject are welcome.
Kasiram.
Dear Ernesto,Back to the Top
We cannot be sure about the availability of the parent unless we
characterise the enzyme responsible for the metabolism. If the parent is
metabolised by CYP 3A4, which is present in the gut, the parent might
not have been absorbed.
If your motive is to compare different formulations of the parent and
if the
metabolite is an active form, I think you can go ahead to compare the
bioavailability based on the metabolite AUC, provided the parent is not
metabolised in the gut. There is no meaning of formulation if the
process is
gut metabolism and in such case you might get similar AUC in all the
formulations.
First pass metabolism comes into picture after absorption, so if the
metabolite formation is due to first pass metabolism, I think you can
use
the metabolite AUC's to compare the formulations of the parent. However
there are many more issues to be considered before we jump to a
conclusion.
I think you will feedback from experts thru pharmpk to get a clear idea
of
what could be done.
Hope this helps,
Thank you for a brain honing query,
Jagannath Kota
Systemic bioavailability depends on both:Back to the Top
For example,
Formulation A:
1: Percent of drug absorbed through the GI membranes into the portal
vein (e.g. 50%)
2: Percent of drug pass through liver without being metabolized (e.g.
50%)
The overall oral bioavailability (F)=50%*50%=25%, for formulation A.
Suppose we have a different formulation B of the same drug, with
1: Same percent of drug absorbed through the GI membranes into the
portal vein (e.g. 50%)
2:Lower percent of drug pass through liver without being metabolized
(e.g. 20%)
Total F=50%*20%=10%
Formulation B will have a higher systemic concentration of its
metabolite, as a result of higher first pass metabolism, despite a
lower F.
Song Di wrote:Back to the Top
"Suppose we have a different formulation B of the same drug, with
1: Same percent of drug absorbed through the GI membranes into the
portal vein (e.g. 50%)
2: Lower percent of drug pass through liver without being metabolized
(e.g. 20%)
Total F=50%*20%=10%
Formulation B will have a higher systemic concentration of its
metabolite, as a result of higher first pass metabolism, despite a
lower F."
I'm a little confused, could you tell me please how could I expect a
different first-pass metabolism for the same drug apart from the logical
between-subject variability?. Don't you think that after the same drug
(usually at the same molar dose) is released from each formulation
(either A or B) any pharmacokinetic event, including properly first-pass process, should be expected to be the same as average?. As per my view, what
count here is the drug release properties (formulations) instead of drug
molecule atributes (same drug = same atributes) such as its metabolic clearance
or hepatic extraction ratio. In fact, this pharmaceutical rational for BE
testing has not been considered sufficiently. Perhaps the ambiguities
in the definition of BA, and consequently in BE, bring about this
discrepancies. In this setting, there should be a responsability to ensure the quality of formulation (viz, biological performance) after any change (pre- and
post-approval during its entire life-cycle), and this kind of effect
rely on its drug release properties. Any comments will be very welcomed. Many
regards,
Jorge Duconge
Jorge:Back to the Top
Some metabolites can be formed even before absoption into the portal
vein, e.g. acidic degradation in the stomach or GI metabolism in the GI
tract or during the process of crossing the GI membrane.
Even if the liver, the different rate of absorption could cause
potential saturation of the enzyme sites.
There are certainly situations where metabolite can be used comparing
different formulations, but not always. Proper examination of the data,
experimental condition, and formulation variation, absoption sites, and
metabolite forming sites (systemic or pre-systemic)may justify the
alternative method. But only on a case-by-case basis.
Di
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