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Dear David
Another issue raised in the Cmax/AUC debate:
There are a number of reports where the concentration-time profile of a drug
has been shown to be different depending on the time of administration
(typically comparisons with drug given at 8 am and 8 pm). What causes the
difference?
One explanation (always remembering that just because something is plausible
doesn't mean it is right) is that decreased gut motility or gastric emptying
at night means drug is only slowly being delivered to a favourable absorption
site (or being retained longer at a favourable one!). A predictive model
taking this into account might be interesting.
Anybody any comments or experiences?
Joe Chamberlain
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I ran into an interesting situation once not while studying drug metabolism
but LDL kinetics. The protocol called for an inpatient study for the first
2 - 3 days after which it was outpatient. During the first two days,
following an IV administration of radiolabeled LDL, frequent blood samples
were drawn including during the night while the subject was sleeping.
In all patients studied, there was a noticable blip at the 24 hour sample,
i.e. there was a nice monoexponential decay up to the 18 hour sample (there
were about 10 samples up to 18 hours starting at 10 minutes), then this
deviation at 24 hours. Samples after 24 hours were daily to one week, then
every other day to 14 - 15 days. In this part of the curve, things were
nice and biexponential as is the case in every LDL kinetic study I've
analyzed.
So what caused this blip? In all cases, the subjects went to bed around
10:00AM meaning there were 1 - 2 samples while they were supine. In all
cases, the 24 hour draw was taken about 30 minutes after they got up in the
morning.
The only thing we could figure to explain this was a redistribution of
plasma volume caused in going from supine to upright.
Anyone else had an experience where they "blamed" changes in plasma volume?
David Foster (the US one, not the Australian one)
CEO, SAAM Institute, Inc.
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David,
There are papers on posture effect on plasma volume such as J
Pineal Res 1998 May;24(4):219-23 Modulation of plasma melatonin
concentrations by changes in posture. Nathan PJ, Jeyaseelan AS,
Burrows GD, Norman TR.
At sleep, the cardiac output drops. What is the effect on renal
function as blood flow decreases, or the liver in xenobiotic
extraction? On Cmax/AUC, as I get older, I notice my gastric emptying
time increases. Maybe we can use asparagus as a probe to study
gastric emptying in different age group.
Bill Tong
Memorial Sloan Kettering Cancer Center
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[Two replies - db]
From: "David M. Foster"
Date: Wed, 27 Mar 2002 18:22:21 -0800
To: david.-at-.boomer.org
Subject: Re: PharmPK Re: Time of day kinetics?
Status: RO
This is fascinating, but I don't think everyone has the aspartic acid gene.
---
From: "A.Sutton"
To: david.aaa.boomer.org
Date: Thu, 28 Mar 2002 09:02:13 -0000
MIME-Version: 1.0
Subject: Re: PharmPK Re: Time of day kinetics?
Reply-to: ASutton.aaa.gcpl.co.uk
Priority: normal
On March 28th Bill Tong wrote: "...as I get older, I notice my gastric
emptying time increases" May I ask how you know this as I am
interested in measuring gastric emptying?
Thanks
Andrew sutton
Guildford Clinical Pharmacology
asutton.at.gcpl.co.uk
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)