David Harbourt
Tel: (919) 966-3787
Fax: (919) 966-0197
Education
Doctorate of Philosophy
Curriculum in Toxicology
Research Advisor: Dr. Philip Smith
Academic Advisor: Dr. Marila Cordeiro-Stone
Dissertation
“The role of intestinal glucuronidation on the disposition and toxicity of mycophenolic acid”
Advisor: Dr. Philip Smith
Mycophenolic acid (MPA) and its prodrug mycophenolate mofetil (MMF) are both used in the clinic as immunosuppressants and for prophylaxis of organ rejection in transplant patients. While this drug has proven useful in this setting, a significant fraction of patients receiving chronic dosages experience delayed-onset diarrhea, which limits the long term effectiveness of their treatment. MPA is eliminated primarily through glucuronidation by the action of UDP-glucuronosyltransferase (UGT) 1A enzymes within the liver and gastrointestinal tract and is subsequently excreted into the biliary tract by the canalicular transporter MRP2 where it is subject to enterohepatic cycling and eventual excretion through the urine as glucuronides. Glucuronidation of MPA results in the formation of the pharmacologically inactive phenolic glucuronide (MPAG) and the potentially labile acyl glucuronide (acMPAG). While the formation of the phenolic glucuronide is the primary method of detoxification of mycophenolic acid in vivo, numerous studies have attempted to link the formation of acyl glucuronides with idiosyncratic adverse drug reactions. While evidence has been inconclusive in directly linking acyl glucuronides with in vivo toxicity, a number of drugs forming acyl glucuronide metabolites have been removed from the marketplace due to idiosyncratic hepatotoxicity and other adverse drug reactions. The purpose of this proposal is to evaluate the differences in the disposition and toxicity of mycophenolic acid and its glucuronide metabolites. It is hypothesized that variable glucuronidation formation and efflux within the gastrointestinal tract results in differences in MPAG formation and thus modulates MPA toxicity. The proposed mechanism involves variable formation of MPAG due to UGT1A isoforms within the intestinal tract. Furthermore, it is also expected that enhanced hepatic and intestinal UGT activity will result in a compensatory upregulation of MRP2 and MRP3 levels leading to enhanced biliary excretion and blood levels of both the phenolic and acyl glucuronide metabolites of mycophenolic acid.