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Dear all,
I have an interesting problem I'd like to discuss with you. I know of a
compound that is mostly metabolized (fm>0.95) and barely excreted
(fe<0.03). The compound is metabolized by 2D6 and 3A4 and at
therapeutic concentrations a partial saturation of the former enzyme
system is observed. Based on this, one would expect no effect on the
elimination of the compound due to decreased renal function. A clinical
study, however, revealed that the compound's CL is correlated with
clearance creatinine, decreasing with renal function. I find this quite
surprising and would like to have other people's experiences and
possible mechanisms.
The only explanation I can come up with is that the renal excretion of
a metabolite is saturated, which in turn saturates the 2D6 and thereby
decreases the clearance of the parent drug. I do not have data on other
2D6 metabolites to confirm this.
Best regards,
Toufigh Gordi
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If you have a case of reversible metabolism, the metabolite being
renally
excreted can accumulate and reverse to the parent. This has been
published for some glucuronides - but reversible metabolism is not
uncommon.
Hope this helps,
Varun
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Dear Toufigh,
You wrote:
> The only explanation I can come up with is that the renal excretion of
> a metabolite is saturated, which in turn saturates the 2D6 and thereby
> decreases the clearance of the parent drug. I do not have data on
other
> 2D6 metabolites to confirm this.
The phrase 'renal excretion of a metabolite is saturated' is somewhat
confusing. I trust that you mean that the elimination of a metabolite is
decreased in case of renal impairment, resulting in higher plasma
concentrations of the metabolite. This higher plasma concentration of a
metabolite may indeed decrease the clearance of the parent drug. Again,
this
is not necessarily due to 'saturation of 2D6', but can be due to product
inhibition, resulting in decreased clearance of the parent drug. Please
note
that the inhibiting compound is not necessarily a metabolite of the
parent
compound; any other endogenous compound or drug which is excreted by the
kidneys may be responsible for the same effect. But a metabolite is
indeed a
likely candidate.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
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Dear Hans,
This discussion is very interesting. Actually I have observed other
situation. A drug is metabolized mainly through conjugation. The drug's
urine fe is about 0.5%. The drug AUC, Cmax is elevated in hepatic
impaired patients than that in healthy subjects. In hepatic impaired
patients, renal clearance of parent drug is also decreased, but
patient's creatinine clearance is normal. What could be the mechanism
here?
Thanks
Lisa
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How much of a change in renal clearance do you see and is this change
clinically significant? In the hepatically impaired patient, what is
the pathophysiology of the problem?
J. Christopher Spell, Ph.D.
Medical Science Liaison - Hematology/Oncology
Global Medical Affairs
Wyeth Pharmaceuticals
Phone: (203) 288-4828
Voicemail: (888) 685-5961 ext. 78647
E-mail: spellj2.-at-.wyeth.com
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Chris,
The change of renal clearance of drug is about 25 to 50% compared to
healthy subjects, but renal excretion of parent drug is minimal, less
than 1%. The degree of hepatic impairment is based on Child-Puph's
score. Most patients has abnormal low plasma albumin concentration.
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Thanks for the response. It would appear then that CLr only plays a
very small role in overall systemic clearance and that those changes in
renal clearance wouldn't cause significant increases in drug exposure
compared with the much larger issue of hepatic impairment in that
particular patient. I assume this patients Child-Pugh score was fairly
high leading to larger changes in albumin.
J. Christopher Spell, Ph.D.
Medical Science Liaison - Hematology/Oncology
Global Medical Affairs
Wyeth Pharmaceuticals
Phone: (203) 288-4828
Voicemail: (888) 685-5961 ext. 78647
E-mail: spellj2.at.wyeth.com
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Dear Lisa,
You stated that the drug is metabolized mainly through conjugation. If
AUC
and Cmax are elevated in hepatic impaired patients, it is likely that
this
process is impaired. Often it is difficult to relate the degree of
hepatic
impairment, e.g. as based on Child-Pugh score, to metabolic functions,
but
perhaps you are 'lucky' that this is the case here.
Since renal clearance of the parent drug is very low, the moderate
decrease
of renal function in the patients is not likely to play a role, in
contrast
to the case of Toufigh Gordi, in which renal impairment was the only
relevant variable between patients (if I interpret this case correctly).
The abnormal low albumin levels in the patients is not likely the
reason of
the increase of AUC. If the parent drug binds to albumin, a decreased
albumin level would imply a decreased fraction unbound, and, as a
result, an
increased clearance (in case of low hepatic extraction) or a decreased
bioavailability (in case of high hepatic extraction). And thus, AUC and
Cmax
would be decreased due to a decreased albumin level.
Any comments are welcome.
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-at-.farm.rug.nl
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Thanks for responding.
In hepatic impaired patients, exposure results are expected. However,
the renal clearance of parent drug (although <1% of total) is decreased
in hepatic impaired patients whose renal function seems normal (normal
creatinine clearance). It is a puzzle to me.
Regards
Lisa
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Lisa writes:
In hepatic impaired patients, exposure results are expected. However,
the renal clearance of parent drug (although <1% of total) is decreased
in hepatic impaired patients whose renal function seems normal (normal
creatinine clearance). It is a puzzle to me.
Take a look at an article written by Sirianni and Pang:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9561488
In short, metabolic clearance and renal clearance are not independent.
They influence each other. The extent of which depends on the relative
values of intrinsic clearance and other features. This is why the FDA
will not rule out renal studies when the drug is eliminated mostly by
hepatic metabolism.
Hope this helps,
Pete bonate
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Johannes and Lisa,
Very interesting discussion. I would also agree that the albumin
binding changes are not leading to increases in AUC and Cmax, but that
the hepatic impairment is leading to these changes. The main question
posed is still why renal clearance changes with alterations in hepatic
function for this particular drug. Is there metabolism in the kidney
that hasn't been accounted for previously in which the much higher
levels of drug may now influence and which creatinine clearance simply
cannot predict?
Christopher
J. Christopher Spell, Ph.D.
Medical Science Liaison - Hematology/Oncology
Global Medical Affairs
Wyeth Pharmaceuticals
Phone: (203) 288-4828
Voicemail: (888) 685-5961 ext. 78647
E-mail: spellj2.at.wyeth.com
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Pete and Christopher,
Thanks for the interesting discussion. I agree your point. In our
study, the creatinine clearance is derived by serum creatinine levels
and that might not reflect the true renal GFR . I did some article
search and found some information may help.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12552488
Lisa
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