- On 1 Feb 2001 at 17:08:21, =?iso-8859-1?Q?=22Masson=2C_=C9ric=22?= (emasson.at.anapharm.com) sent the message

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The following message was posted to: PharmPK

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 - On 2 Feb 2001 at 15:18:28, Khalid Alkharfy (khast6+.-a-.pitt.edu) sent the message

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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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