Download JULS NEWS@UOFT Investigating the Link Between Inflammation

JULS
NEWS@UOFT
Investigating the Link Between
Inflammation and Drug Disposition
Erik J. Bracciodieta
Based on an interview with Dr. M Piquette-Miller, Professor,
Leslie Dan Faculty of Pharmacy at the University of Toronto.
The Piquette-Miller Laboratory studies the effect of disease
on drug disposition. This link is important because many diseases
have an inflammatory component in which cytokines are released
into the bloodstream and alter the gene expression in many tissues.
Diabetes, viral infections, malaria, bacterial infections and various
cancers have an inflammatory component and they are usually
treated with pharmacological products. It is key to understand the
impact of disease on the expression and activity of drug metabolizing enzymes and membrane transporters because inflammation
can alter the efficacy and toxicity of drugs [1, 2, 3, 4].
Over the past several years, the Piquette-Miller lab has found
that many important drug transporters and metabolizing enzymes
are altered in the presence of inflammation. In other words, tissues
may have an altered accumulation of xenobiotics and their metabolites [5], which may cause a drug to be more toxic or less therapeutic.
Accordingly, dosing regimens may need to be adjusted to account
for the body’s altered drug disposition in a variety of disease states.
In the Piquette-Miller laboratory, mostly rodent models of
disease are used to study altered drug disposition during inflammation. Rats or mice are often injected with a disease stimulus such as
lipopolysaccharide for bacterial infection, double stranded RNA for
retroviral infection, malaria infected blood cells or streptozotocin to
induce diabetes. RNA and protein levels of genes of interest are analyzed from important tissues involved in drug disposition including
the liver, kidney, brain, intestine and placenta. Advanced studies use
mass spectrometry or radiolabelled substances to track changes in
xenobiotic concentration throughout the body’s tissues, offering important in vivo information on how diseases affect drug disposition.
Alex M Cressman, a graduate student in the Piquette-Miller
laboratory, is currently studying the impact of malaria infection on
the drug disposition of pregnant mice. One group of mice is infected
with malaria protozoa and the infected red blood cells are isolated
and injected into pregnant mice. The symptoms of the mice and the
fetal outcomes parallel what is observed in human malarial pregnancies [6]. For instance, the fetus in this experimental model are less
vascularized then control fetuses and have lower survival rates [6].
There is little known about drug distribution in pregnancy models
and pharmacological effects on fetal development. This study examines the expression of CYP enzymes and ABC drug transporters in
the maternal brain, liver, kidney and placenta along with fetal brain
A flow diagram showing what factors to consider when studying differential drug transporter regulation.
and liver. Few, if any, studies have investigated altered gene expression and its involvement in drug disposition in fetal organs. It would
be interesting to see what genes are differentially changed in utero
and if they can explain clinical observations of poor fetal outcome
in the malaria disease state. This experiment is in progress and will
produce a paper later this year.
References
1. Anger GJ, Magomedova L and Piquette-Miller M. Impact of acute streptozotocin-induced
diabetes on ABC transporter expression in rats. Chemistry and Biodiversity 2009; 6: 1943.
2. Petrovic V and Piquette-Miller M. Impact of polyinosinic/polycytidylic acid on placental and
hepatobiliary drug transporters in pregnant rats. Drug Metabolism and Disposition 2010; 38:
1760.
3. Petrovic V, Wang JH and Piquette-Miller M. Effect of endotoxin on the expression of placental drug transporters and glyburide disposition in pregnant rats. Drug Metabolism and
Disposition 2008; 36: 1944.
4. De Souza R, Zahedi P, Badame RM, Allen C, Piquette-Miller M. Chemotherapy dosing schedule influences drug resistance development in ovarian cancer. Molecular Cancer Therapy
2011; 10: 1289.
5. Wang JH, Scollard DA, Teng S, Reilly RM and Piquette-Miller M. Detection of P-glycoprotein
in endotoxemic rats by 99mTc-Sestamibi imaging. Journal of Nuclear Medicine 2005; 46: 1537.
6. Neres R, Marinho CRF, Goncalves LA, Catarino MB, Penha-Goncalves C. Pregnancy outcome
and placental pathology in Plasmodium berghei ANKA infected mice reproduce the pathogenesis of severe malaria in pregnant women. Public Library of Science One 2008; 3(2): e1608.
Journal of Undergraduate Life Sciences • Volume 6 • Issue 1 • Spring 2012
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