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Hi, everyone,
I am working on the Oral Pharmacokinetics of Sparfloxacin(Fluoroquinolone
antibiotic) in Swiss mouse.
Dose administered is 30 mg/kg. The peak plasma concentration(Cmax) observed
in my lab is around 6.5 - 7.0 =B5g/ml.
However, Danniponn the originator of Sparfloxacin has reported a very low
Cmax values.
Has anyone come across any other published data on sparfloxacin in Mouse.
Yati Chugh Ph.D
Sr.Scientist:Pharmcokinetics.
Wockhardt Research Centre.
Aurangabad, India.
e.mail : yatichugh.aaa.hotmail.com
ychugh.-at-.wockhardtin.com
Hi,
I would like someone to clarify one of my queries:
Is area under the curve for a compound depends upon it's tissue
distribution??
i.e A compound like Sparfloxacin has a good tissue distribution. Will it's
area under the curve will be more as compared to another compound which has
a poor tissue distribution.
Yati Chugh Ph.D
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Cmax is very dependent on the method and site of administration. I
would first compare your AUC values to the prior data. If your results
are with 25% of the previous results, then I would consider them
compariable. If they are not:
1. Look closely at differences in the mice (similar weight?, strain?)
2. How was the drug administered (IV, IP, gavage, etc)? If IV,
how rapid was the injection?
3. Did the serum/plasma sampling differ. One study my have
obtained serum immediately after IV injection while the other study
may have waited 5 minutes.
> Has anyone come across any other published data on sparfloxacin in Mouse.
Have you tried the manufacturer?
> Is area under the curve for a compound depends upon it's tissue
> distribution??
AUC to a large extent is proportional to tissue distribution. However,
there are many other factors that effect entry into cells and tissues.
The factors include protein binding, lipophilicity, ability to cross
cell membranes, etc.
>
> i.e A compound like Sparfloxacin has a good tissue distribution. Will it's
> area under the curve will be more as compared to another compound which ha=
s
> a poor tissue distribution.
Unlikely - the AUC is measured in serum. If one looks at a series of
similar compounds. An inverse relationship between serum AUC and tissue
penetration would be expected.
> Yati Chugh Ph.D
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>I would suggest that the AUC will be proportional to DOSE
>and inversely proportional to CL.
Don't pussyfoot around here. Its not a suggestion. Its an item of religious
certainty. AUC (0-infinity) or during a steady state dosing interval has
nothing, nada, zero to do with volume of distribution :-)
Note also that AUC is also proportional to F (extent of bioavailibility) as
well as Dose and Clearance.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.html
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[A few replies - db ;-)]
From: "Bachman, William"
To: "'PharmPK.aaa.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Re: AUC question - Sparfloxacin
Date: Thu, 11 Mar 1999 07:32:59 -0500
MIME-Version: 1.0
But seriously, what do you really think, Nick?
( thanks for making me laugh at 7:30AM :)
regards,
Bill
---
Date: Thu, 11 Mar 1999 14:48:40 +0100
From: "Guentert, Theodor W. {PRNK~Basel}"
Subject: RE: PharmPK Re: AUC question - Sparfloxacin
To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
MIME-version: 1.0
Good to see that there are still some people who can clear the mist.
Theo
---
From: Allan Evans
To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Re: AUC question - Sparfloxacin
Date: Fri, 12 Mar 1999 09:43:31 +1030
MIME-Version: 1.0
AUC is not dictated by the volume of distribution term. However, don't
think that clearance and distribution are always independent. If elimination is
occuring from a peripheral compartment, then the clearance of a drug can be
permeation-rate limited (eg if membrane permeation clearance is less than
intrinsic clearance). This can occur for highly polar drugs. In this case, it
is the distribution process (movement into tissue) that governs clearance. In
these circumstances, an increase in permeability (ie a ditribution papameter)
will produce an increase in clearance. AUC will therefore be dictated by a
'distribution phenomenon'.
Allan Evans
School of Pharmacy
University of South Australia
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> From: Allan Evans
> Subject: RE: PharmPK Re: AUC question - Sparfloxacin
> Date: Fri, 12 Mar 1999 09:43:31 +1030
> AUC is not dictated by the volume of distribution term. However, don't
> think that clearance and distribution are always independent. If
>elimination is
> occuring from a peripheral compartment, then the clearance of a drug can be
> permeation-rate limited (eg if membrane permeation clearance is less than
> intrinsic clearance). This can occur for highly polar drugs. In this case, it
> is the distribution process (movement into tissue) that governs clearance. In
> these circumstances, an increase in permeability (ie a ditribution papameter)
> will produce an increase in clearance. AUC will therefore be dictated by a
> 'distribution phenomenon'.
This is a good point. The distribution phenomenon you refer to can be
described as inter-compartmental clearance. It is indeed often not realised
that it is usually assumed that elimination takes place from the central
compartment (whether one is using non-compartmental methods or not). If
elimination in fact takes place in a peripheral compartment then changes in
elimination clearance can masquerade as a change in volume of distribution
(even when estimated using NCA methods). This seems to me to be one
reasonable explanation for the apparent decrease in volume of distribution of
digoxin when quinidine is given. It is known without question that quinidine
decreases renal clearance of digoxin and it seems quite feasible that renal
elimination is kinetically "deeper" than the central compartment. I am aware
that it has been claimed from in vitro studies that quinidine displaces
digoxin binding and that is the reason why volume of distribution decreases
but I prefer to invoke just a single mechanism - a decrease in clearance of
digoxin from a non-central compartment.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Park Road, Private Bag 92019, Auckland, NZ
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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