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Is it possible for metabolite to have earlier Tmax than the parent
compound when the parent compound is dosed iv or po in simple
formulations? What could be going on when this was observed?
Thanks.
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The following message was posted to: PharmPK
I think a combination of gut and liver metabolism could produce this.
Gut metabolism would take place primarily during the absorption phase,
generating metabolite along with that produced by the liver or other
metabolizing tissues from drug in plasma. After absorption is more or
less
complete, some gut metabolism could take place with drug that
partitioned
back into the enterocytes from the plasma, but in general, I would not
expect such an amount to be very large.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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The following message was posted to: PharmPK
Dear Cindy
With IV dosing, this possibility is remote.
With PO dosing, following conditions may result into such effect:
1. If the metabolism is occuring in the gut wall/GIT lumen, and the
permability of the metabolite is higher as compared to the parent
molecule,
2. If the metabolism is occuring in the gut wall/liver by enzymes
which are
saturable and drug concentration is very high as compared to the
enzymes,
initially higher concentration of metabolites may appear in the blood
flowed by higher concentration of drug.
Regards
Rajesh
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How much early is the Tmax of metabolite over parent? Lower protein
binding and tissue affinity for metabolite over parent and/or
mechanism based inhibition of CYP enzymes (suicide inhibition) could
result in such an effect.
Kasiram.
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Hello Cindy,
Whats the dose at which the compound was administered? Is the dose
falling in linear kinetics range?
When the compound is administered by oral gavage at higher doses
there is a possibility for such a phenomenon (where saturation in
biotransformation pathways can occur and kinetics become
nonlinear).Administering a dose which comes in the linear kinetics
range may result in the reversal of this trend. So, its worth
performing an oral pharmacokinetic study at a low dose.
Hope this helps.
Good luck
Ravi
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When dosed iv, both metabolite and parent compound peaked at the 1st
time point sampled: 5 minute. When dosed po, metabolite Tmax=0.5h and
parent Tmax=1h. PO dose levels were 25mg/kg and 100mg/kg in rats.
Do you know of any examples of metabolite having earlier Tmax than
the parent compound?
Thanks,
Cindy
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The following message was posted to: PharmPK
Also check Diacerein.
Regards
Rajesh
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