CTMSDG proudly announces next meeting February 2nd (Westbrook, CT)

CTMSDG's next meeting will be February 2 at Water's Edge in Westbrook, CT from 6 - 8:30. Free registration ends 1/24/16.

Fatemeh Akhlaghi, Pharm.D., Ph.D., a Professor and the Ernest Mario Distinguished Chair in Pharmaceutics in the College of Pharmacy, University of Rhode Island.

Dr. Akhlaghi is a pharmaceutical scientist with expertise in drug metabolism, clinical pharmacology, translational sciences and pharmacokinetic/pharmacodynamic (PKPD) modeling. She has earned PhD degree from the University of Sydney, Australia and carried out postdoctoral fellowships in Sydney Australia and Cambridge, United Kingdom. The goal of her research is to understand the sources of variability in drug disposition and effect with a long term goal of devising personalized therapy for existing or new pharmacological agents. Her laboratory carries a full range of clinical pharmacology investigations including design and implementation of clinical pharmacokinetic studies, quantification of drug concentration and metabolites using LC-MS/MS as well as analysis of pharmacokinetics data by standard and population pharmacokinetic modeling softwares. In addition, she is the director of the graduate program in Pharmaceutics and Pharmacokinetics and Principal Investigator on two NIH funded grants.

Presentation Title: Pharmacokinetic Consequences of Metabolic Syndrome: Challenges and Opportunities for Proteomic Mass Spectrometry

Metabolic syndrome and associated conditions (obesity, diabetes and nonalcoholic fatty liver disease) is a major health problem worldwide and in the United States. The interest of our laboratory is on the effect of metabolic syndrome on drug disposition and action. The concentration of cyclosporine metabolites, a substrate for Cytochrome P450 (CYP) 3A4, was significantly lower in kidney transplant recipients with diabetes (Akhlaghi, Ther Drug Monitor, 2012). Moreover, the concentration of atorvastatin lactone, another CYP3A4 was significantly lower in patients with diabetes mellitus (Dostalek, Clinical Pharmacokinetics, 2012). Using human liver with diabetes, we have observed P450 3A4 protein expression and enzyme activity (midazolam hydroxylation and testosterone 6-beta hydroxylation) were significantly lower in diabetic livers (Dostalek et al. Br J Pharm 2011) and this results in reduced biotransformation of atorvastatin lactone to oxidative metabolites (Dostalek, Clinical Pharmacokinetics, 2012). Recently, we have created a bank of human livers from 106 donors with diabetes matched based on age, gender and ethnicity with non-diabetic donors. We have characterized the presence of nonalcoholic steatohepatitis (NASH) by pathological staining in collaboration with the liver research unit in Brown University. Significantly efforts are underway to perform a comprehensive analysis of the effect of metabolic syndrome on the expression drug metabolizing enzymes and transporters using a time of flight instrument with SWATH capabilities. This technique provides an excellent opportunity or investigate the upregulation and downregulation of various proteins simultaneously in different fractions of hepatocyte (microsome, cytosol, nuclear fraction, membrane fraction). We are currently trying to understand whether protein glycation that is associated with diabetes has a pronounced effect on the proteomic analysis by SWATH.



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