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Dear Colleagues:
Four oral doses (CMC formulation) were tested over a
100-fold range. At lower dosed female AUC was 4-5
times greater than male but with increasing dose and
treatment duration male and female AUC differences
reduced to 2-fold and become negligible at the highest
dose. These are AUC values at the highest dose:
Female AUC = 8400 on day 1 and on day 28 = 3200
Male AUC = 1600 on day 1 and on day 28 = 2800
Does anyone seem this before? Why male and female AUC
moves in opposite directions? Does anyone have any
reference for sex-dependent metabolism/elimination
induction? Or something strange is happening with
bioavailability? BTW, the repeat of this experiment
produced the same results.
Rostam
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Dear Rostam,
Without giving you a literature reference, but in our routine assay of
metabolic stability investigations using liver microsomes, we often
observe
gender specific metabolism. In many cases, microsomes derived from male
animals show a higher metabolic rate than from female animals.
So, for one part of your question (lower maleAUC than femaleAUC and
increasing AUC at increasing doses), variation and saturation of
metabolic
processes could be a reason.
best regards,
Philip
Philip Lienau
Schering AG
Research Pharmacokinetics
Tel.: +49 - 30 - 468 - 18507
Fax: +49 - 30 - 468 - 12238
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Dear Rostam,
Kedderis and Mugford (1998) described significant sex-dependent
differences in metabolism (CYP expression levels) of various drugs, as
well as species-differences. Your temporal changes may also be related
to changes in CYP expression levels (differential induction and
suppression in the genders), as well as possible hormonal effects on
expression.
Adrian Sheldon
In Vitro ADMET
Charles River Labs
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Hi Rostam,
The result you got is not surprising. We also observed a similar
trend in NCE in rats. If you still have samples remaining then
estimate the concentration of metabolites. You will get the answer
for gender difference in metabolism.
cheers,
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Is gender-dependent metabolism in animals of relevance to the
clinic? i.e. does gender difference in PK in animals translate to
gender difference in humans?
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Dear Bunny:
You tend to see more incidences of gender-dependent
metabolism in animals (particularly rat) than in
human. To some extent, this observation is documented
and it is believed in large that has to do with
different expression levels of P450 enzymes (different
CYPs) in male and female rats. I relate the question
of relevance to gender-dependent difference in
humans/clinical situation to your specific situation
(case-by-case basis) and the stage of the program
development? For example, do you see the gender
difference in more than one animal species? Say rat
and dog or rat and monkey? Are you about to select the
clinical candidate among a limited number of lead
compounds with similar efficacy range but differences
in gender-dependent metabolism? You may be willing to
sacrifice a little efficacy for "a more
favourable/cleaner" compound in terms of PK/Tox.
My specific question with this regard was targeted to
the fact that is it possible to have an induction of a
specific CYP in one sex and inhibition of the same CYP
in another sex? Alternatively, if two isoenzymes are
involved in metabolism of a compound one may get
induced in one sex and the other may get inhibited in
another sex. Probably the answer is some of the
publication that a few of my colleagues suggested and
I have not read yet (in order) but if some know please
provide your input.
Rostam
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Just thought I should throw my 2c into the discussion...but shouldn't
we all be referring to "Sex" dependent PK, as Im not too sure that a
male living/acting as a female makes their physiology become
"female". IMHO "gender" needs to be used *very* carefully in
medicine and science, and as I recall, the Journal of Clinical
Pharmacology and Therapeutics had a bit of an Editorial on this issue
a few years back...
David
David Foster, PhD
NHMRC Research Officer
Department of Clinical and Experimental Pharmacology
Faculty of Health Sciences
The University of Adelaide
Adelaide, South Australia 5005
Tel: +61 08 8303 5985
Fax: +61 08 8224 0685
Email: david.foster.at.adelaide.edu.au
http://www.adelaide.edu.au/Pharm/index.htm
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David, you are absolutely correct. We should be
talking about sex dependent PK. Thanks for the note.
Rostam
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