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Hi!
I have a pharmacokinetic question, being myself not a classical
pharmacokineticist, but familiar with the subject a little bit.
In a rat in vivo model injecting a drug IV through a jugular vein cannula,
a drug metabolite plasma concentration vs time was studied. In
phenobarbital pretreated rats, the Cmax and the apparent t1/2 were found
to be increased(4fold) and reduced respectively while the AUC is increased
only 40% as compared to untreated rats. I think I can reasonably conclude
from increased AUC and Cmax that the rate and extent of drug metabolism
has increased substantially. My real question is does the decreased t1/2
(~4fold less than the untreated group) signify increased rate/extent of
metabolism?...(obviously trying to ascertain 2B induction by PB)
Thank in advance for the response.
Partha.
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Hi,
You can not come to that conclusion only by observing prolonged t1/2.
Metabolite binding to plasma or tissue may have also been altered
resulting in changes in the volume of distribution, consequently,
increase in the t1/2 value.
Regards
Majid
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Dear Partha
From your results it is certain that the metabolism of the parent
compound has been dramatically increased. It is reasonable to assume
that this was mediated by one of the isoforms which phenobarb is known
to induce. As regards the metabolite itself, the reduced t1/2 infers a
higher clearance of the metabolite itself, but you cannot assume that
this is as a result of increased metabolism as there are many possible
explanations (phenobarb induction, autoinduction....).
Hope this helps
Malcolm Bohm
Clinical Pharmacokineticist
Tel +44 (0) 1509 64 4878
Fax +44 (0) 1509 64 5586
E-mail Malcolm.bohm.aaa.charnwood.gb.astra.com
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Partha:
Is the drug you are studing renally excreted? If so you may want to look at
the side effects of pentobarbital on renal function. for that manner, look
into other commonly used anesthetics and their effect on renal function,
specially if they are co-administered with any drug eliminated through
kidneys.
The high AUC and other PK parameters or measured concentrations may be
tainted by the effects of any coadministered anesthetics. An example of this
effect can be seen in an full peer reviewed article that is coming out this
month. The reference is:
"The effects of Anesthetics on the Biodistribution of Drugs in Rats: A
Carboplatin Study." Cancer Chemotherapy and Pharmacology Journal, issue 6,
volume 40, p.521-525.
As you know, carboplatin is renally excreted and the effects observed in this
study may give you an insight on the effects of coadministered anesthetics in
renally excreted drug studies.
Good luck,
Alfredo R. Sancho
PK Imaging Ctr.
Los Angeles, CA
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