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Hi, All:
I am now using male and female beagle dog liver microsomes to do metabolic stability assay and I find a strange compound which showed significant gender difference on the stability. The in vitro t1/2 in female dog liver microsomes is about 186 min, but only 6.7 min in male. Based on my experiences, only rats have significant gender differences on CYP450s activity, and dogs almost no any differences. Could anyone know the possible reason about this strange phenomenon? Thanks!
Btw: I have double-checked this data and the positive control also included in this experiment which showed normal as usual.
Jian
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The following message was posted to: PharmPK
Dear Jian, You
wrote:
"Based on my
experiences, only rats have significant gender differences on CYP450s activity,
and dogs almost no any differences." The last part of your statement needs more
careful considerations and may not be entirely true. Amacher and Smith (J. chromatogr,
419, 61-73) showed that hepatic CYP in naive beagle dogs appeared as 3 isozymic
groups in females whereas, male dogs had 2 main groups with 2-3 subgroups and
they identified sex-related differences in chromatographic behaviour of the
major groups. Occasionally, we see a compound that shows sex-dependent PK in
dog which also correlates with in vitro stability data. We also see a more
pronounced sex-dependent difference for the same compound in rat both in vitro
and in vivo. Any sex-dependent differences were observed using rat or human liver
mircrosomes? What about in vivo?
Rostam
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Dear Rostam:
Thanks for your help. The sex-dependent differences were not observed using rat or human liver microsomes and we don't have in vivo data yet. I have searched this phenomenon with Pubmed database, but there are few papers reported this defferences except the one you provided. Do you have other references about this strange thing and have those different subgroups been identified?
Jian
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