The investigator's long-term career objective is to become an independent clinician-scientist and educator in the fields of pediatric pharmacology, pharmacogenetics and pediatric hematology/oncology. This application involves formal didactic training in clinical research skills and a focused research proposal designed to form the foundation for a career in clinical research. Through participation in the Indiana University K30 program, the applicant will receive the didactic training necessary for a research career in clinical pharmacology. The candidate has the full support of the Chairman of Pediatrics and the Director of the GCRC and will perform her research in an outstanding clinical research environment. The proposed projects aim to determine which enzymes are involved in vinca alkaloid disposition and whether genetic polymorphisms in these enzymes and the membrane transporters that carry the vinca alkaloids are predictive of disposition, efficacy and toxicity. Despite the long history of vinca alkaloid use in oncology, the precise roles of the cytochrome P450 enzymes in their disposition remain largely uncharacterized. This is important because there is no definitive explanation for the significant variability in the pharmacokinetics of these drugs. As a result, pharmacokinetic or pharmacogenetic parameters that might predict vinca alkaloid toxicity and outcome have not been identified.
The first aim of this proposal involves identification of the major metabolites of the vinca alkaloids, the enzymes involved in their production, and quantification of Michaelis Menten kinetic parameters for these enzymes.
The second aim i nvestigates the impact of pharmacogenetic polymorphisms in pertinent drug metabolizing enzymes and transporters on vinca alkaloid pharmacokinetics, toxicity, and efficacy in pediatric and adult cancer patients. Through these projects, this investigator will work toward her long-range research goal of understanding how genetic polymorphisms in drug metabolizing enzymes, receptors, and transporters influence the efficacy and toxicity of drugs in pediatric and adult cancer patients.
| Topletz, Ariel R; Dennison, Jennifer B; Barbuch, Robert J et al. (2013) The relative contributions of CYP3A4 and CYP3A5 to the metabolism of vinorelbine. Drug Metab Dispos 41:1651-61 |
| Egbelakin, Akinbode; Ferguson, Michael J; MacGill, Emily A et al. (2011) Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 56:361-7 |
| Dennison, Jennifer B; Mohutsky, Michael A; Barbuch, Robert J et al. (2008) Apparent high CYP3A5 expression is required for significant metabolism of vincristine by human cryopreserved hepatocytes. J Pharmacol Exp Ther 327:248-57 |
| Dennison, Jennifer B; Renbarger, Jamie L; Walterhouse, David O et al. (2008) Quantification of vincristine and its major metabolite in human plasma by high-performance liquid chromatography/tandem mass spectrometry. Ther Drug Monit 30:357-64 |
| Renbarger, Jamie L; McCammack, Kevin C; Rouse, Caroline E et al. (2008) Effect of race on vincristine-associated neurotoxicity in pediatric acute lymphoblastic leukemia patients. Pediatr Blood Cancer 50:769-71 |
| Dennison, Jennifer B; Jones, David R; Renbarger, Jamie L et al. (2007) Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther 321:553-63 |
| Dennison, Jennifer B; Kulanthaivel, Palaniappan; Barbuch, Robert J et al. (2006) Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos 34:1317-27 |
