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Assuming a single dose or drug (A) is administered, and converted into an
intermediate metabolite (B) which is converted to a final metabolite (C).
My question is regarding the partial metabolic clearance:
1- Which of the following equation is valid, if any, to calculate the
partial metabolic clearance of metabolite C:
CLmet C = Ae0-inf. (C)/ AUC0-inf. (parent A)
CLmet C= Ae0-inf. (C)/ AUC0-inf. (met. B)
Clmet C= Ae0-inf. (C)/ AUC0-inf. (met. A+B)
2- Is this parameter valid even when the metabolic pathways are not fully
characterized?
Any insight or references would be appreciated.
Eric Masson
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The following message was posted to: PharmPK
Dear Eric:
Your scenario is as follows:
A------------>B------------>C (assuming that this is the only metabolic
pathway occurring)
If you are interested in the calculating the formation clearance of C [CLf
C], and the conversion of B------->C is the RATE LIMITING STEP, you should
use:
CLf C= Ae0-inf. (C)/ AUC0-inf. (met. B), assuming that C is totally renally
eliminated.
To calculate the renal clearance of C [CL r C], use the following equation:
CLr C= Ae0-inf. (C)/ AUC0-inf. (met. C)
However, if the rate limiting step is the conversion of A----------->B, you
cannot directly calculate the CLf C from A, and you may need to administer
the intermediate metabolite B (if possible), then calculate the CLf C as:
CLf C= Ae0-inf. (C)/ AUC0-inf. (met. B)
If the metabolic pathways are not well characterized, then the parameters
that you will be getting may not be accurate since the assumptions have been
violated.
You may want to administer the parent drug and measure the metabolites in the
urine and do a mass balance study.
Hope this helps.
Thanks,
Khalid Alkharfy
University of Pittsburgh.
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