Jones, Jeff

Research

Professor Jones received his PhD in 1987 from the University of Washington, where he worked with Professor William Trager in the Department of Medicinal Chemistry. After postdoctoral work with Professor Trager and with Professor W. W. Cleland at the University of Wisconsin, he joined the Faculty of the Department of Pharmacology and Physiology at the University of Rochester. He was promoted to Associate Professor in 1996. He joined the WSU Department of Chemistry in August, 1998.

Work on aldehyde oxidase (AO)-  AO continues to be of increasing importance in drug metabolism and an early understanding of binding and kinetics will help us avoid expensive failures in the clinic.  Such failures have already been documented for AO, and a general awareness of the problem now exists.  However, models for AO’s role in human metabolism are particularly significant since animal models fail to predict human AO (hAO) affinities or clearance values.  The major impact of this research will be in decreasing drug development time and the cost in human life associated with incomplete information when a drug candidate enters clinical trials.

Important Outcomes– All three of these aims will provide information that can be used to construct a molecular representation of how AO binds inhibitors and, binds and oxidizes, substrates. Overall, the studies in this grant will achieve two overriding outcomes; 1) allow for the more rapid design of drugs that are AO substrates for life-threatening disease, and 2) help prevent failures in the clinic resulting from DDI’s and poor PK predictions.

Work on P450 Enzymes- The overriding goal of this work is to understand the factors that are important in time dependent inhibition (TDI), and to use this knowledge to predict when TDI will have the potential for clinical adverse reactions. At present, in vitro TDI analyses lack the resolution for quantitative prediction of clinical outcomes. For example, in vivo drug-drug interactions (DDIs) for many drugs are over-predicted. Further, the regulatory agencies can require clinical data irrespective of weak or negative in vitro TDI results. The possible origins of poor predictions include inadequate in vitro analyses, unreliable in vivo parameters, and complex biochemical mechanisms.

In order to investigate the impact of complex kinetics on TDI parameter estimation, new kinetic schemes will be developed, simulations will be conducted, and in vitro data collected and analyzed with a novel numerical method. We hypothesize that by using our numerical method and appropriate kinetic schemes for the analysis of time-dependent inhibition data in vitro, we can better determine kinetic parameters for in vivo pharmacokinetic models. Specifically, A) Both rat and human preparations will be used to collect in vitro TDI data, since parameters from these studies will be used in Aim 3 for IVIVCs. Specifically, expressed enzymes, microsomes and hepatocytes will be used to generate CYP TDI data for clinically relevant inhibitors, B) Models will be derived for non-Michaelis-Menten kinetic schemes and sequential metabolism, and will be used to analyze data from 1A, and C) The origin and impact of quasi-irreversible inactivation will be studied.

Important Outcomes– Together, the studies proposed will for the first time, incorporate known kinetic complexities into models to predict TDI mediated DDIs. Mechanistic details of TDI kinetics will be explored to parameterize the underlying kinetic rate-constants for TDI. In particular we aim to understand how differences in the molecular environment affect substrate and product binding and dissociation, and enzyme degradation. Finally, this information will be used to parameterize novel in vivo models for TDI. These models will be used to explore the impact of dosing regimens on clinical DDIs.

Publications

Visit Professor Jones research website for an up-to-date list of publications.