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For a drug that has multi-phasic elimination, what can be the plausible
explanations) for higher apparent clearance after multiple-dose (steady
state) compared to after a single-dose? (other than product-inhibition or
auto-inhibition possibilities)
Thanks
Soraya
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[A reply and a restatement of the question ;-) - db]
From: Fredéric Massiere
Date: Wed, 26 Jun 2002 09:16:59 +0200
To: david.aaa.boomer.org
Subject: Re: PharmPK Difference in the apparent clearance after SD versus MD
Dear Soraya,
Could it be that the drug cause induction of the expression of one or
several metabolic enzymes, a process that requires time for onset ?
Best regards,
Frederic MASSIERE
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From: soraya.madani.at.pharma.novartis.com
Date: Wed, 26 Jun 2002 09:09:52 -0400
To: david.-at-.boomer.org
Subject: Re: PharmPK Difference in the apparent clearance after SD versus MD
Sorry-
I wrote the question incorrectly.
The question is:
For a drug that has multi-phasic elimination, what can be the plausible
explanations) for lower apparent clearance after multiple-dose (steady
state) compared to after a multiple-dose? (other than product-inhibition or
auto-inhibition possibilities)
Soraya
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Frederic-
Thanks for your reply.
I really can not explain higher exposure after MD compared to after SD. It
is about 50% higher. Induction would most likely result is opposite
effect. Wouldn't you think? Given the drugs metabolism auto-inhibition or
product inhibition can not explain this
Soraya
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Assuming IV route and significant accumulation upon multiple dosing,
protein binding could be an issue.
Srikumaran K. Melethil, Ph.D., JD
Professor, Pharmaceutics and Medicine
University of Missouri- Kansas City
203B Katz Hall (School of Pharmacy)
Kansas City, MO 64110
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Dear Soraya,
Earlier you said that you have high apparent clearance with MD over SD
and now you say that you have higher exposure with MD over SD. Are they
not contadicting? How ever, if the first statement is true it may be
that protein binding of your drug is less and that with MD its getting
saturated. If the second statement is true, it may be that your
elimination process is getting saturated with MD.
Regards,
Kasiram.
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Do you mean lower apparent CL after MD? If so, co-substrate
depletion is a possibility.
Other possibilities are:
1. Saturable first-pass
2. Saturable CL at higher concentration
Hope this helps,
Varun
Varun Garg, Ph.D.
Vertex Pharmaceuticals, Inc.
130 Waverly Street
Cambridge, MA 02139
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My mistake. What I meant was" higher exposure after MD (lower CL/F)
compared to SD"
Thanks
Soraya
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