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Dear all,
I have come across an interesting phenomenon. In the elimination of
ramiprilat, active metabolite of ramipril, the initial phase is quite
rapid with half life of 7-17 hrs.
The terminal phase is very prolonged with t1/2 reported from various
sources as >50 hrs, >120 hrs, etc. In a study that we have run there
were concentrations above LOQ 3 weeks after dosing.
The strange thing is that when a decreased dose was used (3-fold less
than on the first occasion), same level lingering concentrations showed
up after 3 weeks as in the high-dose study.
There PK parameters were also different when corrected for a dose: both
AUC0-t and Cmax of the lower dose were lower than expected.
Can anyone provide an insight as to the possible mechanism of this
occurrence.
Thanks in advance.
Matthew Wasserman, B. Sc. Pharm., M. Sc.
Associate Pharmacokineticist, Biometrics
Apotex Research Inc. - Biomedical Division
440 Garyray Drive, Toronto,
Ontario, Canada M9L 1P7
Telephone: (416)749-9300 Ext. 8163
Fax: (416)401-3181
Email: mwasserm.at.apotex.com
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The following message was posted to: PharmPK
Dear Mathew,
This is due to saturable binding to plasma and/or tissue ACE. please see
J Pharmacokinet Biopharm 1989 Oct;17(5):529-50 for further insight.
If you have various doses with PK data after single and multiple doses,
you
can use one or more of the modeles described in that paper to
understand the
disposition of the unbound drug.
Sriram
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The following message was posted to: PharmPK Dear Mr. Matthew,
It appears that ramiprilat is exhibiting a biphasic phenomenon. May be
the drug is undergoing extensive distribution into the tissues during
the initial phase because of which you are observing a faster
elimination during that phase. May be the distributed drug is getting
slowly released into the systemic circulation after distribution
beacuse of which you may be observing a slow elimination during second
phase.
You are saying that when you used dose 3 times less than the initial
dose you saw the same accumulation what you observed with the highest
dose. on the contrary you are mentioning in your next sentence that you
are finding a lower AUC and Cmax. Aren't your statements mutually
contradicting ?
Regards
Ravi Kanth Bhamidipati
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Dear Ravi Kanth Bhamidipati:
Thank you for your response.
It is not the accumulation but the concentration levels of ramiprilat
at advanced times post dose are similar at the high and the low doses.
AUC 0-t and Cmax are observed parameters and they are in fact lower for
the lower dose after applying the dose adjustment.
My own tentative explanation to that is that ACE binding sites are
saturated at both doses and the same amount of the drug "disappears"
into this very deep compartment. Percent-wise, this amount accounts for
a larger proportion of the small dose as compared to the large dose.
As the sampling is not covering sufficient time to account for the
dissociation of the ACE-drug complex, the observed AUCt and Cmax of the
lower dose will be non-proportionally lower as compared to the higher
dose.
However, any other explanation for this phenomenon is appreciated.
Matthew Wasserman
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The following message was posted to: PharmPK
Dear Matthew Wasserman,
another good article to your question is
Tight binding of ramiprilat to ACE: consequences for pharmacokinetic and
pharmacodynamic measurements.
Int J Clin Pharmacol Ther. 1995 Dec;33(12):631-8. by D. Brockmeier.
Hope this helps.
Joachim Juettner
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