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The following message was posted to: PharmPK
Dear All,
We have a one compound which is stable in In-vitro Rat Liver metabolic stability study (8% Metabolized in RLM). When we carried out the same compound for in-vivo Oral pharmacokinetic study in rats, we found high intravenous Clearance (80 mL/min/kg) & Bioavailability (%F) was found to be 80%. What could be the possible reasons even after high Clearance i.v., metabolically stable with high bioavailability?
Thanking you and Regards
NageswaraRao M
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Dear NageswaraRao M,
Metabolic stability can be under estimated when drug is undergoing Phase-II metabolism as RLM has only Phase-I CYP enzymes (except GLN). Here 8% stability may be under estimated?.Carry out phase-II metabolism study.
or some other reason could be differences in RLM CYP enzymes expression Vs in-vivo CYP enzyme expression.
Systemic bioavailability depends on Fg,Fa,and Fh. If you are getting good bioavailability it means there is no loss of drug during absorption,via gut metabolism and hepatic metabolism (minimum first pass effect) after oral administration.
Once this molecule reaches to the systemic circulation (without first pass i.e. high bioavailability) now it will be subjected to high rate of phase-II metabolism in your case which may be giving high drug clearance 80ml/min/kg.
Bottom line message is that if molecule has no issue with absorption and it is not undergoing first pass metabolism after oral administration then its bioavailability will be as high as I.V administration means 100%.And still molecule can show high clearance.
Hope this will help
Regards,
Rahul Vats
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Hi Nageshwar,
Blood to plasma paartitioning may answer high CL?
Regards,
AB Rao
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The following message was posted to: PharmPK
Dear Nageshwara:
Will you please provide the IV and oral dose?
If the difference in IV and PO dose is high (more than 3 to 10-fold), there may be chances of saturation of CYP enzymes at oral dose (Nonlinear PK) which resulted in high %F.
You can confirm this by conducting the study at IV: 1 mg/kg and PO: 3 mg/kg dose or at identical doses.
For in vitro metabolic stability related issue, it will be better if you can check the nonspecific microsomal binding at used protein and test item concentration.
Regards,
Prashant Nigade,
Sai Advantium, Pune
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High tissue distribution
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