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Colleagues,
Recently we conducted a study in cynomologus monkeys of a novel drug
development candidate utilizing a iv -oral crossover design with C-14
labeled compound (presumedly labeled in a chemical and metabolically stable
position). When comparing serum C-14 AUCs, we determined an iv to oral
ratio of about 0.6 to 7.5. However, comparing total C-14 excreted in urine
produced a ratio of approximately 1.0. Which value is more likely to
represent the true extent of oral absorption and why? This compound does
undergo extensive biotransformation, both phase I and II, and its E
(subscript: H )has been calculated to be about 0.65.
Thanks,
Roy McQuinn
rlmcquinn.at.mmm.com
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[Two replies - db]
Sender: gmould.-a-.dial.pipex.com
Date: Thu, 29 Jul 1999 09:23:55 +0100
From: Graham Mould
To: PharmPK.-a-.boomer.org
CC: Multiple recipients of PharmPK - Sent by
Subject: Re: PharmPK which to believe
Dear Roy
Measuring C14 is always frought with problems. As an initial thought, I
suppose you have checked your methods, ie checking your extraction
methods from either serum, plasma or whole blood, and looking at
quenching. Are you sure you are measuring total radioactivity or parent
drug.
Graham Mould
Guildford Clinical Pharmacology Unit
Royal Surrey county Hospital
Guildford, UK
---
X-Sender: ahoffman.at.cc.huji.ac.il
Date: Thu, 29 Jul 1999 15:57:55 +0300
To: PharmPK.-a-.boomer.org
From: "Dr. Amnon Hoffman"
Subject: Re: PharmPK which to believe
Dear Roy,
You better relay on the urine data. This is because the volume of
distribution of the drug and the metabolites is not the same. Therefore, if
the metabolite(s) profile is different following iv and PO administration,
the AUC values that are affected by the volume of distribution is not
reliable. On the other hand, the total amounts of the drug + metabolites
that are collected in the urine overcome the potential differences in Vd.
The urine data can also be somewhat problematic if the ratio of renal
excretion is different following the two modes of administration.
Amnon Hoffman PhD
Head, Clinical Pharmacy Education
The Hebrew University of Jerusalem, School of Pharmacy
Tel: 972-2-6758667, Fax: 972-2-6436246
P.O.B. 12065, Jerusalem 91120, Israel
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