Ph.D., Wayne State University, 1981
Drug disposition in humans, drug-drug and drug-diet interactions, pharmacokinetics, inter- and intra-individual variability in pharmacokinetics, bioanalytical chemistry
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. My lab developed and validated a novel drug cocktail as a probe for phenotyping human subjects for key xenobiotic-metabolizing enzyme activities. With this approach six 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, 2C19, 2D6, and 3A4) as well as other enzymes associated with xenobiotic disposition.
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. Currently my group is using our probe drug cocktail to characterize drug-drug and drug-supplement interactions in humans. We also are using cells transfected with specific human transporters to define the molecular basis of a drug-drug interactionwe have observed in humans. Finally- we are measuring patient drug levels and performing pharmacokinetic modeling to support two cancer chemotherapy clinical trials.
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. PMID: 16103443
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. PMID: 17164373
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: 2619-2624, 2008. PMID: 18843002