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Hello,
Usually, when a compound is metabolized to a
metabolite and a PK metabolic interaction occur, the
plasma levels of parent will be higher and of
metabolite lower.
I found a paper when both levels of parent and
metabolite are higher after a PK interaction. As time
it seems that clearance of metabolite is not changed
and is less probable a change of VD, can you explain
that?
link to article:
http://www.blackwell-synergy.com/links/doi/10.1046/j.1365
-2125.2000.00290.x/pdf (db)
Thank you,
vlase laurian
Vlase Laurian
Dept. of Pharmaceutical Technology and Biopharmaceutics
Faculty of Pharmacy
University of Medicine and Pharmacy "Iuliu Hatieganu"
13, Emil Isac
Cluj-Napoca, Cluj 3400, Romania
vlaselaur.-a-.yahoo.com
online on Yahoo Messenger
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Vlase,
Concerning the interaction between loratadine and ketoconazole, the
effect could be explained by ketoconazole acting as a dual inhibitor
of both metabolism and transport. If biliary efflux is blocked there
can be an increase in liver metabolism because of the longer hepatic
residence time. If the efflux of metabolites is inhibit they can
accumulate still further. Ketoconazole is known to be an inhibitor of
PGP as well as CYP3A (and other enzymes).
Cimetidine is not known to inhibit biliary efflux (although it is an
inhibitor of OCT). In this case the result is consistent with
inhibition
of metabolism without an effect on transport of parent or metabolites.
Just my thoughts...
All the very best,
Bernard
Bernard Murray, Ph.D.
Senior Research Investigator
Drug Metabolism, PCS, PPD, GPRD, Abbott Laboratories, Chicago, USA
Bernard.Murray.-at-.abbott.com
I have seen this before in drug-drug interaction studies.Back to the Top
In our case, we found that the interacting drug increased the
absorption of our drug, possibly either by changing the pH or by
inhibiting an enzymatic absorption barrier in the gut, namely CYP3A4
and/or PGP. In that case, you may see the phenomenon you are
describing.
Hope that helps."
Partha Roy, PhD
Forest Labs.
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Consider the case that an efflux transporter (e.g. P-gp) is inhibited:
you
get more parent drug into the systemic circulation which may lead to
higher
concentrations of both parent and metabolite(s) once the metabolizing
enzyme(s) become saturated.
Hope that helps.
Regards,
Bernhard J. Ladstetter, Ph.D.
Head of Global Non-Clinical DMPK
Global Preclinical R&D
Institute of Drug Metabolism and Pharmacokinetics
Merck KGaA
Am Feld 32
D-85567 Grafing
Germany
Phone: +49 (0)8092-700810
Mobile: +49 (0)172 8661247
Fax: +49 (0)8092-700899
e-mail: bernhard.ladstetter.-a-.merck.de
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