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A drug was given IV infusion for 1 hour, daily for 5 days. The peak
concentrations was determined at the end of infusion. The peak
concentrations at day 5 were much lower than those at day 1 (from 10 to
50%, mean 36%).
This drug undergoes hepatic biotransformation to its corresponding
glucuronide by uridine diphosphate glucuronosyltransferases and the
metabolites are mainly excreted into bile. T1/2 (a)=0.5h, t1/2(B)=8h.
CL=24L/h, V=140L,
The enzyme induction could be a major reason for decreased peak
concentrations. Any other reasons? since some peak concentrations at day 5
drop so profoundly in 1 h.
Thanks.
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Five days is too short of a period for significant enzyme induction to have
occurred, so I don;t believe that would be the cause in this instance
(assuming no previous exposure to this drug).
With such a large volume of distribution, this seems to be more of a
distribution issue.
One piece of information not clearly included is when, after the end of the
infusion, was the sample concentration obtained. Although a strict reading
would say immediately upon stopping the infusion. If the sample were
obtained from the blood through the administration tubing, you could be
getting some contamination of the sample with drug solution remaining in
the tube.
Back to the distribution, since your data suggests a two cmpt model (with a
distribution phase) subsequent administrations (with drug already in the
system, since the half life is 8 hours) would cause a 'reduction' in the
definition of this distributive phase to the point that it would not be as
pronounced. To avoid this problem, you should sample 30 to 60 minutes
after the end of the infusion, which should result in more consistent data,
thus avoiding the changing nature of the distributive phase. Using the
peak for multicompartment models often presents this type of problem.
Chuck Collins
Charles C. Collins, Ph.D.
Associate Professor of Pharmaceutics
Duquesne University Mylan School of Pharmacy
President - Duquesne University Faculty Senate
collinsc.-a-.duq.edu
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[A few replies - db]
Date: Thu, 16 Sep 1999 16:34:48 +0200
From: Mats Karlsson
Organization: Uppsala University
X-Accept-Language: en
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK Re: Reduced peak concentrations
All other issues aside. Five days can well be a reasonable time for
autoinduction. Actually, for cyclophosphamide we've seen full development of
autoinduction withing 3 days. The drug was given as a constant infusion over
92 hours, so the autoinduction was clear and the half-life of the enzyme could
be estimated quite well.
Best regards,
Mats Karlsson
---
X-Sender: navb.-at-.popin.ncl.ac.uk
Date: Thu, 16 Sep 1999 16:02:57 +0100
To: PharmPK.aaa.boomer.org
From: Alan Boddy
Subject: Re: PharmPK Re: Reduced peak concentrations
Hi
Can't agree with that first statement. Induction of metabolism can be
demonstrated within 24 hours with some drugs (cyclophosphamide/ifosfamide).
Hope this is useful
alan
Cancer Research Unit
Medical School
University of Newcastle
Newcastle upon Tyne
NE2 4HH
Tel 0191 222 8233
Fax 0191 222 7556
http://www.ncl.ac.uk/~ncru/
---
Date: Thu, 16 Sep 1999 16:05:51 +0100
From: Ulrika Svensson
Reply-To: ulrika.svensson.-a-.biof.uu.se
Organization: Uppsala University Uppsala Sweden
X-Accept-Language: en,sv
To: PharmPK.at.boomer.org
Subject: Re: reduced peak concentrations
Enzyme induction can occur within five days. An example of this is
artemisinin autoinduction where a five-fold decrease in AUCs is observed
after a five fold oral administration.
It seems to me that the drug is a low extraction drug. The clearance is
then dependent on clearance intrinisic and protein binding. I would
suggest that the reason for decreasing concentrations might be due to a
change in either of these two parameters.
Ulrika Svensson
Div of Pharmacokinetics and Pharmaceutics
Dept of Pharmacy
Uppsala University
Sweden
--
From: Varun Garg
To: "'PharmPK.at.boomer.org'"
Subject: RE: PharmPK Re: Reduced peak concentrations
Date: Thu, 16 Sep 1999 11:54:41 -0500
Tretinoin (All-trans retinoic acid) undergoes a significant enzyme induction
within 5 days (Adamson, Sem. Hematology, 1994:31, 14-17).
Another reason could be reduced protein binding due to competition from
metabolite(s) for the binding sites. This would increase Vd and CL both.
Varun
~~~~~~~~~~~~~~~
Varun Garg, Ph.D.
Aronex Pharmaceuticals, Inc.
8707 Technology Forest Place
The Woodlands, TX 77381-1191
Tel: 281-367-1666 x317
Fax: 281-367-1676
email: vgarg.at.aronex-pharm.com
~~~~~~~~~~~~~~~
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Autoinduction can also occur within a few days with carbamazepine.
Ron Kavanagh
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