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The following message was posted to: PharmPK
Hello
I was wondering if anyone has experience in conducting pre-clinical
pharmacokinetic studies in animal models of diabetes mellitus . The
most
common model is streptozotocin or alloxan induced diabetic rat but
this model
does not represent metabolic problems associated with type 2 diabetes
and
related conditions (fatty liver disease etc). More importantly is
there any
model available to study the alteration in in Cytochrome P450 expression
resulted from hyperglycemia or diabetes.
Many thanks and I look forward to hear from you.
Fatemeh
Fatemeh Akhlaghi, PharmD, PhD
Associate Professor in Pharmacokinetics
Biomedical and Pharmaceutical Sciences (BPS)
University of Rhode Island
125 Fogarty Hall, 41 Lower College Road
Kingston, RI 02881, USA
Phone/Fax: (401) 874 9205/(401) 874 2181
Email: fatemeh.-at-.uri.edu
Laboratory Website: http://www.uri.edu/pharmacy/faculty/aps/akhlaghi/
index
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Dear Fatemeh,
This field is not exactly in my expertise; but through my reading I
came across some good review articles. I am listing them below.
1) Rees DA, Alcolado JC. Animal models of diabetes mellitus. Diabet
Med. 2005 Apr;22(4):359-70.
2) Leiter EH, von Herrath M. Animal models have little to teach us
about type 1 diabetes: 2. In opposition
to this proposal. Diabetologia. 2004 Oct;47(10):1657-60.
3) Roep BO, Atkinson M. Animal models have little to teach us about
type 1 diabetes: 1. In support of
this proposal. Diabetologia. 2004 Oct;47(10):1650-6.
There is also the recent edition of the book "Animal models of
Diabetes Mellitus" by E. Shafrir.
I hope this helps.
Murad Melhem, Ph.D.
Cognigen Corporation
Buffalo, NY
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The following message was posted to: PharmPK
Fatemeh,
Type in diabetes and CYP2E1 in Pubmed and you'll get a plethora of
references.
Susan E. Shoaf, PhD
Asst. Dir. PK/PD
Otsuka Pharmaceutical Development & Commercialization, Inc.
Rockville MD
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Hi Fatemeh
I have followed the field of development of PPAR agonists very
closely (Pioglitazone, rosiglitazone etc.) The animal model most
frequently used for efficacy assesment has been the db/db mouse and
the ob/ob mouse, both of which have mutations in the leptin receptor
and thus manifests the symptoms of Type -2 Diabetes. However, the
species that has been used for the PK is SD rat only most of the
times. It is certainly possible to carry out PK studies in both these
models too.
Hope that helps.
Geeta Sharma
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Typical and more reliable animals models for type II diabetes are ob/
ob and db/db mice (hyperglycemic, very high insulin resistant, fatty
liver and lipid dismetabolism). For rats studies zucker fa/fa (not
hyperglycemic but insulin resistant, lipid dismetabolism and fatty
liver) and zucker ZDF (includes also high hyperglycemia).
These animals (db/db mice for example) have liver over-expression of
PPAR alpha and PPAR alpha-related enzymes (check on PUBMED) Since
PPAR aplha stimulation increases microsomes synthesis and peroxisomal
beta-oxidation would not to be surprizing that also P450 activity
could be increased.
Ciao
Dr Roberto Conti
Sigma-Tau
Dep. of Endocrinology and Metabolism
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