Peng Hsiao
Research Assistant,
Jashvant D Unadkat Lab,
University of Washington
Biography
Peng Hsiao is a PhD candidate in the Department of Pharmaceutics at the University of Washington, in Seattle. He received his BA degree in Biology from the University of Puget Sound and his MS degree in Pharmaceutics from University of Washington. Peng has thirteen years of research experience in biotechnology and pharmaceutical sciences, including medical device development.
He worked developing the continuous blood gas monitor at Abbott Laboratories for three years, followed by ten years at NeoRx Corporation (now Poniard Pharmaceuticals) developing radio-immunotherapeutic agents for the treatment of cancer. Peng’s research interest and PhD thesis work is focused on P-glycoprotein (P-gp) based drug interactions at the blood-brain barrier, their clinical relevance, and our ability to predict such interactions with in vitro methods and in vivo animal models. With the ongoing non-invasive positron emission topography (PET) imaging studies to measure P-gp-based drug interactions at the human BBB in Dr. Jashvant D Unadkat’s Lab, Mr. Hsiao has the unique opportunity to quantitatively compare these in vitro and in vivo animal methods to human data.
Abstract
P-gp based drug interactions at the blood- brain barrier: Fact or fantasy?
P-gp (170 kDa), an ATP dependent efflux transporter, extrudes out of cells structurally unrelated drugs of diverse therapeutic categories. The human P-gp is localized on the luminal surface of the blood brain barrier (BBB) endothelial cells, intestinal epithelia, the renal proximal tubule, the bile canalicular membrane of the hepatocytes, and the placenta syncytiotrophoblast. This anatomical localization, together with its broad substrate profile, accounts for the significant role P-gp plays in drug distribution, absorption, metabolism and excretion.
The in vivo importance of P-gp at the BBB has been well-demonstrated by studies in mdr1a (-/-) or mdr1a/b (-/-) mice. Administration of P-gp substrate drugs to these mdr1 (-/-) mice results in dramatic increase in the brain distribution of these drugs. Similar elevation in brain:blood ratio in the rat or the wild type (wt) mice is observed when P-gp activity at the BBB is inhibited using chemical inhibitors such as cyclosporine A (CsA).
While the importance of P-gp at rodent BBB has been well-demonstrated, the importance of P-gp in distribution of drugs across the human BBB and drug interactions at this site has not been fully evaluated. Due to safety and ethical reasons, it has not been possible to measure in vivo human BBB P-gp activity. With the development by our laboratory of a non-invasive, Positron Emission Topography (PET) imaging method to measure P-gp-based drug interactions at the human BBB, a quantitative in vitro - in vivo comparison of drug interactions at the brain P-gp barrier is now possible.
This presentation focuses on current known P-gp based drug interactions at the blood-brain barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies in vitro or in vivo using rodents. The ability to predict drug-drug interactions at the human BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing toxicity of non-CNS drugs.
Supported by: NIH grant GM32165, ITHS TL1 Multidisciplinary Predoctoral Clinical Research Training Program, PHS2271.
