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Dear All,
We have a one compound which is stable in In-vitro Rat Liver metabolic stability study (8% Metabolized in RLM).
The same compound when dosed to rat and dog showed clearance of 80 & 36 mL/min/kg respectively .
But the bioavailability was found to be 80 % in both the species.
Further we have carried out the following experiments and observations as follows :
Phase II metabolism - No phase II metabolism confirmed by hepatocyte study.
Protein binding - No microsomal protein binding (fu microsomes is almost 1)
Blood to plasma partitioning ratio ~ 1.0
What could be the reason for high bioavailability of the compound with such high clearance ?
Thanking you and Regards
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What about renal clearance? Have you looked in urine for metabolites or excretion of unchanged drug?
-Rachel
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Dear Palacharla:
As per my opinion there are two possibilities:
1) Non-linear PK: High oral dose may leads to saturation of either metabolism or elimination pathways. This can be rechecked either by conducting study with identical IV and PO doses or the difference between IV and PO dose generally should not exceed 3-fold
2) Billiary clearance with enterohepatic recirculation: Have you observed multipeaks in both IV and PO profile?
Regards,
Prashant Nigade
Sai Advantium, Pune
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Dear
The drug show lower protein binding and and may ionized rapidly and cleared through through kidney or may follow any other route of metabolism. It is better to check metabolites in urine.
Dr Zafar
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10 % of the dose is excreted in urine as unchanged drug , and none excreted in feces.
regards,
Raghav.
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Hi,
How is about tissue binding?
XD
Hi,
I would do a mass balance study.
XD
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