Research Interests
Xenobiotic metabolism, drug-drug and drug-diet interactions, pharmacokinetics, inter- and intra-individual variability in pharmacokinetics
The rate of metabolism of drugs and other foreign chemicals (xenobiotics), and the specific enzymes and pathways involved in this metabolism, are major determinants of the biological effects of xenobiotics. Variability in the expression of key xenobiotic-metabolizing enzymes is a major contributor to inter-individual variation in the therapeutic and toxic effects of chemicals. We have developed and validated novel drug cocktail as a probe for phenotyping human subjects for key xenobiotic-metabolizing enzyme activities. With this approach five drugs are administered to human subjects and blood and urine samples are obtained and analyzed for particular drug metabolites.
These analyses utilize LC-MS/MS assays. The levels of these specific metabolites provide a measure of the activities of several cytochrome P450s (CYP1A2, 2C9, 2D6, and 3A4) as well as other enzymes associated with xenobiotic metabolism. Beyond this baseline phenotyping, we also are applying this approach to studying the modulation of xenobiotic-metabolizing enzymes in humans. Drugs or other xenobiotics may compete for the same enzyme, decreasing the net rate of metabolism. Other compounds may induce certain xenobiotic-metabolizing enzymes, resulting in significant increases in metabolic rate. Either of these alterations can cause significant changes in therapeutic and toxicologic responses following drug or chemical exposure.
By determining the effects of diet, nutritional supplements, or other drugs or chemicals on the metabolism of the drug probe we can predict drug-drug or other interactions which could adversely affect an individual's response to therapy. Two projects are currently underway to determine if dietary supplements alter prescription drug metabolism. In one of these projects we are studying a supplement with supposed cancer chemopreventive activity, and in the other study we are characterizing the inter-individual variability in the effect of a widely-used herbal product on drug metabolism activities.
The findings from these studies can be of immediate clinical value in that significant alterations of xenobiotic-metabolizing enzymes must be taken into consideration when advising patients about use of these supplements. The other application is that any observed alterations in xenobiotic-metabolizing enzyme activities in these human studies will be followed by in vitro work and experiments in animal models to characterize the mediators and mechanisms of the resultant alterations.
Reed, G.A., Peterson, K.S., Smith, H.J., Gray, J., Sullivan, D., Mayo, M.S., Crowell, J.A., and Hurwitz, A. A phase I study of indole-3-carbinol in women: Tolerability and effects. Cancer Epidem., Biomarkers & Prev. 14: 1953-1960, 2005.
Reed, G.A., Arneson, D.W., Putnam III, W., Smith, H.J., Gray, J.C., Sullivan, D.K., Mayo, M.S., Crowell, J.A., and Hurwitz, A. Single- and Multiple-Dose Administration of Indole-3-carbinol to Women: Pharmacokinetics Based on 3,3’-Diindolylmethane. Cancer Epidem., Biomarkers & Prev.15: 2477-2481, 2006.
Reed, G.A., Sunega, J.M., Sullivan, D.K., Gray, J.C., Mayo, M.A., Crowell, J.A., and Hurwitz, A. Single-dose pharmacokinetics and tolerability of absorption-enhanced 3, 3’-diindolylmethane in healthy subjects. Cancer Epidem., Biomarkers & Prev 17: in press, 2008.
Reed, G.A., Peterson, K.S., Stucky, C-.C., Sunega, J.M., Gray, J., Sullivan, D., Mayo, M.S., and Hurwitz, A. The Hurwitz cocktail: Tolerability and interaction study with a 5-drug cocktail. Submitted for publication.
Gregory A. Reed, Ph.D
.Associate Professor
Department of Pharmacology, Toxicology and Therapeutics
The University of Kansas Medical Center
MS1018
3901 Rainbow Boulevard
Kansas City, KS 66160
Phone: (913) 588-7513
Fax: (913) 588-7501
E-Mail: greed@kumc.edu
Curriculum Vitae in PDF Format
Updated 9/5/08
©
The University of Kansas Medical Center