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Dear all,
I would like to hear some of your thoughts.
I noticed some gender differences in PK of one drug. Females seem to
have higher AUC values.
The elimination of this drug is metabolism and in the literature it is
suggested that the blood clearance fraction is 58% of total liver
blood flow, indicating an intermediate, but close to high, extraction
ratio for this dug.
For that clearance is dependant primarily on liver blood flow.
As blood flow is different between males and females can this be one
possible explanation for the different AUC values?
Thx in avance,
L.
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The following message was posted to: PharmPK
Lidija
> I would like to hear some of your thoughts.
> I noticed some gender differences in PK of one drug. Females
> seem to have higher AUC values.
> The elimination of this drug is metabolism and in the
> literature it is suggested that the blood clearance fraction
> is 58% of total liver blood flow, indicating an intermediate,
> but close to high, extraction ratio for this dug.
> For that clearance is dependant primarily on liver blood flow.
> As blood flow is different between males and females can this
> be one possible explanation for the different AUC values?
Certainly you can say that CL is different between males and females.
It is
likely therefore, given the relatively high extraction of this drug that
perfusion will be an important factor.
It is important to note that it is more likely to be the patients lean
body
mass (rather than sex) that predicts this difference in CL. There is a
growing body of evidence that CL is related to a patients' LBW (see
Han et
al CPT 2007;82:505-508) and we know that LBW is greater in males than
females. So, this seems to be an expected observation.
Steve
--
Professor Stephen Duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 913 Dunedin
New Zealand
E: stephen.duffull.aaa.otago.ac.nz
Design software: www.winpopt.com
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Dear Koren,
The expression of metabolic enzymes (CYPs) in males and females differ
and this is attributed to PK differences to a major extent.
Substrates for CYP3A4 exhibit higher clearance in women, and this
difference even persists after correcting for physiological factors
such as body
weight [Meibohm B, Beierle I, Derendorf H. How important are gender
differences
in pharmacokinetics? Clin Pharmacokinet 2002;41:329-42.]
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Dear Koren,
For the drug with high E (Extraction ratio), hepatic clearance is
dependent of hepatic blood flow (where Clint>>Q). hence, blood flow
difference between male and females may also be a possible explanation
for the different AUC values.
Regards,
Martin J Gnanamuthu,
Drug Metabolism and Pharmacokinetics,
Orchid Research Laboratories Ltd,
476/14, Old Mahabalipuram Road,
Sholinganallur,
Chennai-119.
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Dear Koren
I would like to know if the observation you have made i.e. "difference
in PK between males and females" is this in preclinical or clinical
studies.
I would like to make comment about PK differences in preclinical
species. I have observed these differences when working on some
compounds
In case of preclinical species:
In rats and mice we find these differences with some compounds, for
example most of the TZD's show this feature in mice and rats. As we go
up the species ladder the differences in AUC gets reduced. It is
important to note that there is not much variation in absolute
bioavailability of the compound but the AUC is higher.
One of the main reasons is because of differences in metabolism of
compound is different in males and females. This we confirmed by
preparing Liver microsomes from male and female rats. When the
compound was incubated in both the microsomes it was observed that the
percentage of compound remaining from male rats is lower than the
female rats indicating that metabolism plays a role here.
Regards
Pavan
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The following message was posted to: PharmPK
Hi Koren,
There are several physiological factors that results variable drug
disposition.
Recent literature reveals that Steroids activate hPXR (Pregnane-X-
Receptor), as a result
there will be induction of most drug metabolizing CYPs, UGTs and
certain transporters.
Females express higher levels of sex hormones than males. This could
be another
explanation for variable drug metabolism in pregnant women compared to
post-partum
studies.
Thanks
Sripal
Sripal Reddy Mada, M.Pharm, Ph.D
Research Assistant Professor
University of Pittsburgh School of Pharmacy,
716 Salk Hall, 3501 Terrace Street
Pittsburgh, PA 15261
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The following message was posted to: PharmPK
Lidija
> I would like to hear some of your thoughts.
> I noticed some gender differences in PK of one drug. Females
> seem to have higher AUC values.
> The elimination of this drug is metabolism and in the
> literature it is suggested that the blood clearance fraction
> is 58% of total liver blood flow, indicating an intermediate,
> but close to high, extraction ratio for this dug.
> For that clearance is dependant primarily on liver blood flow.
> As blood flow is different between males and females can this
> be one possible explanation for the different AUC values?
Certainly you can say that CL is different between males and females.
It is
likely therefore, given the relatively high extraction of this drug that
perfusion will be an important factor.
It is important to note that it is more likely to be the patients lean
body
mass (rather than sex) that predicts this difference in CL. There is a
growing body of evidence that CL is related to a patients' LBW (see
Han et
al CPT 2007;82:505-508) and we know that LBW is greater in males than
females. So, this seems to be an expected observation.
Steve
--
Professor Stephen Duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 913 Dunedin
New Zealand
E: stephen.duffull.-at-.otago.ac.nz
Design software: www.winpopt.com
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