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Dear all,
Please find below a case study for which I would like to have some
help in the result interpretation...
A compound was administered in monkeys both orally and intravenously
with or without a co-administration of ketoconazole. Ketoconazole did
not have any impact on the PK compound administered IV: AUC ratio
equal to 1 and no change of the elimination half-life. On the
contrary, ketoconazole did have a major impact on the PK compound
administered PO: Cmax ratio and AUC ratio higher than 6 but still no
modification of the elimination half-life. The conclusion was that
ketoconazole alter the first-pass but not systemic metabolism of the
compound... That's for sure but I would like to look deeply in the
involved mechanisms to explain these results.
My idea is the following: the first-pass of that compound was
essentially intestinal and the enzyme(s) involved are mainly present
in the intestine and poorly in the liver.
What do you think ? Do you have any other assumptions that could
explain these results ?
Thanks for your time.
Francois.
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Dear Francois,
Ketoconazole is a known inhibitor of both CYP enzymes and p-
glycoprotein transmembrane pump (maybe other transporters are also
involved). This could explain your observations if your compund is a
good substrat for the the p-gp.
You can do search on the subject and i am sure you will find many
papers in that subject.
Regards
Abdullah Al-Mohizea
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The following message was posted to: PharmPK
Dear Francois,
Note that ketoconazole is an inhibitor of CYP3A and PGP in cynomolgus
monkey. Ward et al have a 2001, and 2004 paper in drug metab.
Disposition that might be useful to you.
Best Regards,
Mike Cameron
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The following message was posted to: PharmPK
Dear Francois,
One possible explanation for the extensive gut metabolism but
very small contribution by liver involves UGT conjugation. Some of the
UGT isotypes (like 1A10, and 2B15) are highly expressed in the small
intestine but not in the liver (Strassburg CP, J. Biol. Chem. 275(46):
36164 (2000)). At least one article reports of ketoconazole being an
inhibitor of morphine glucuronidation by UGT2B7 (Takeda S, Inhibition
of UDP-glucuronosyltransferase 2b7-catalyzed morphine glucuronidation
by ketoconazole: dual mechanisms involving a novel noncompetitive
mode. Drug Metab Dispos. 2006 Aug;34(8):1277-82.).
Is your compound a possible substrate for conjugation? We've
been experimenting with GastroPlus simulations using a physiological
distribution of UGT enzymes in the gut. You might want to try some of
those types of simulations to see if this explanation is plausible.
Mike
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Dear Francois,
The first thing comes to mind when someone says ketoconazole: CYP 3A
or pg-p inhibition. That is possible and may explain your results.
Are there any possibilities of absorption changes (may be due to
chemical interaction in the GIT in presence of keto)?.
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