Dr. Smith’s research interests are in correlating pharmacokinetics and metabolism of drugs with their pharmacodynamics and toxicity.  Research efforts in this area include in vitro studies and in vivo animal experiments aimed at understanding mechanisms of processes that influence drug disposition and toxicity.   Where possible, transitional studies in human subjects are conducted to demonstrate clinical relevance and the potential application to humans.    A primary emphasis in the laboratory is the process of glucuronidation, the major Phase II metabolic pathway where the sugar, glucuronic acid, is coupled to drugs and other xenobiotics.  The major project areas are described below.

Glucuronidation is one of the most common conjugative metabolic pathways for endogenous compounds, drugs and other xenobiotics.  Glucuronidation directs the excretion and distribution of xenobiotics such that glucuronides usually have small volumes of distribution and are often substrates for active transport into the urine and excretion in bile.  Biliary excretion is one step in the enterohepatic recycling (EHC) of drugs that are glucuronidated.  EHC of drug glucuronides requires cleavage with glucuronidase and it has the effects of reducing the apparent clearance (i.e. increasing systemic exposure if drug is reabsorbed) and increasing intestinal exposure to the drug.  Therefore, EHC has been implicated as enhancing intestinal toxicity by cytotoxic drugs such as the antitumor agent irinotecan.  Previous approaches to the problem of intestinal toxicity, with the integration of drug metabolism, biliary excretion and EHC have had some success, though predictive relationships or approaches to reduce intestinal toxicity are often still elusive.   A critical component of drug-induced intestinal toxicity that has heretofore not been incorporated into the scheme, is the ability of intestinal epithelial cells to form glucuronides and excrete glucuronides, thus providing intrinsic resistance to toxicity at the cellular level.  Mycophenolic acid (MPA, immunosuppressant) and SN-38 (antitumor), are active compounds derived from prodrugs MMF and irinotecan, respectively, that rely upon glucuronidation for elimination.  The following global hypotheses are being addressed in this NIH funded research: i) Intestinal UGTs have a critical role in modulating exposure of intestinal epithelial cells to drugs, thus influencing their of gi toxicity, and ii) Intestinal UGTs and transporters modulate the bioavailability and EHC of drugs, such as MPA and irinotecan.

The role of glucuronidation on the absorption and disposition of antiHIV drugs that rely upon this metabolic pathway is being investigated.   With funding from NCCAM, botanical and herbal medicines that make claims or have reports of their ability to modulate glucuronidation are being evaluated in vitro and in vivo for possible botanical-drug interactions.  Zidovudine, abacavir and mycophenolic acid are being studied with botanicals to determine if competitive inhibition of metabolism occurs,  whether botanicals may be inducers of intestinal or hepatic metabolism or if the botanicals may influence EHC.   These in vitro studies are being translated to human clinical trials in collaboration with the Center for AIDS Research on campus.

Dr. Smith also has an interest in and has initiated methods to quantify proteins using liquid chromatography-mass spectrometry (LC-MS).  Our current focus is to develop approaches to quantify the UGT isoforms of the 1A family that have been difficult to measure by typical semi-quantitative Western blot methods, in part due to the inability to prepare specific antibodies.  These novel LC-MS methods will permit studies of the UGT 1A family, particularly those isoforms present in the intestine and colon, which are relevant to the research direction described above.

Recent publications on PubMed

Dr. Smith received his B.S. in Pharmacy from the University of Illinois, Chicago Medical Center, and his Ph.D. in Pharmaceutical Chemistry with an emphasis in pharmacokinetics in 1985 from the University of California, San Francisco.   After postdoctoral studies at the National Institutes of Health in Bethesda, MD, as a National Research Council Fellow, he joined the faculty of the College of Pharmacy at the University of Texas at Austin.   In 1992 he moved to the School of Pharmacy at the University of North Carolina at Chapel where he is presently an Associate Professor in the Division of Molecular Pharmaceutics.  Dr. Smith’s primary research efforts funded by NIH are directed toward understanding factors influencing the disposition, pharmacokinetics, reactivity and potential role in toxicity of labile acyl glucuronide metabolites, the role of glucuronidation in intestinal toxicity of drugs and the modulation of drug glucuronidation by botanicals/herbal remedies.   His laboratory also has interests that include investigating drug disposition in cystic fibrosis, studying the glucuronidation of immunosuppressive drugs, and the analysis of drugs, metabolites, proteins and peptides in biological matrixes.   He is currently serving as Member-at-Large for the Pharmaceutical Sciences Section of AAAS, is a Council Member of the International Society for the Study of Xenobiotics, and is a member of the USP Dietary Supplements: Bioavailability and Nutrition Absorption Expert Committee.   He is past recipient of the Faculty Development Award in Pharmacology and Toxicology from the PhRMA Foundation.    Dr. Smith was Co-Chair of the 1997 ISSX meeting in Raleigh, NC, has served as an ad hoc reviewer for NIH study sections and provides consultation to the pharmaceutical industry.  Dr. Smith is a member of the editorial advisory board for the Journal of Pharmacology and Experimental Therapeutics and Current Drug Metabolism, and serves as a reviewer for the journals Drug Metabolism and Disposition, Biochemical Pharmacology, Pharmaceutical Research, the Journal of Pharmaceutical Sciences, Analytical Chemistry and others