Kent Kunze

Associate Professor and Chair

Department of Medicinal Chemistry, Medicinal Chemistry Faculty

Expertise: Cytochrome P450, Drug Interactions, Drug Metabolism, Distribution and Transport

Telephone: (206) 685-3543

Email: kkunze@uw.edu

Website: PubMed

Education

  • B.S. 1977, University of Washington
  • Ph.D. 1981, University of California at San Francisco

Research Overview

The interaction between biological systems and an administered drug are marked by a complex series of events and effects. In general, the removal of a drug from the body is accelerated by enzyme-catalyzed steps which transform the drug molecule into a series of metabolites which are more readily eliminated from the body. These biotransformation reactions occur primarily in the liver and are principally mediated by cytochrome P450 enzymes.

It is now evident that the participation of the cytochrome P450 enzymes in biotransformation reactions is a two-edged sword leading to both desirable and undesirable consequences. The cytochrome P450 enzymes exhibit broad and overlapping substrate specificities and product selectivities. In addition, their distribution and levels of expression in different tissues exhibits high inter-individual variability which may be dramatically altered by exposure to drugs and environmental contaminants. As a consequence, it has often been difficult to associate a particular biochemical endpoint such as toxicity or drug clearance with a particular P450 isozyme or sub-family of isozymes. Knowledge of the role played by each isozyme is a prerequisite to understanding the participation of these enzymes in toxicity and drug metabolism.

One of the primary goals of our research is to develop simple in vitro models and methods which may be used to understand and predict the impact of human cytochrome P450-dependent oxidation reactions on drug clearance and toxicity. One method we are developing is the use of isozyme-specific inhibitors which may be used to determine which P450 enzymes are responsible for the metabolism of a given drug. Ideally, an arsenal of isozyme-specific inhibitors will be developed to allow for the rapid identification of those isozymes responsible for the metabolism of a new drug or environmental contaminant.

The approach we are using to address this problem is designing isoform selective “suicide substrates” for each P450 enzyme by incorporating certain types of reaction chemical substructures into known isoform selective substrates. A suicide substrate is a compound which irreversibly inactivates an enzyme when a reactive species is unmasked during an attempted oxidation step, leading to covalent attachment of the substrate to the enzyme active site. Since the active site of the enzyme is covalently modified by these types of inhibitors, a second focus of this research is to identify amino acids which occupy the active site of each enzyme.

A second major goal in our laboratory is to explore the molecular basis of metabolic drug-drug interactions and develop a framework which may be used to predict the likelihood of an interaction at early stages in drug development. The change in the rate metabolism of one drug caused by the presence of a second competing drug in vitro can provide qualitative information about drug-drug interactions. In order to apply this knowledge to the prediction of a drug interaction in vitro, a number of parameters – such as inhibitory potency, enzyme specificity and concentration of the inhibitory drug – need to be determined or estimated. The scope of this research includes metabolically-based drug-drug interactions, and to establish kinetic and pharmacokinetic models which relate inhibitor concentrations in plasma to the magnitude of inhibitory effect on drug clearance.

Selected Publications

  • Rock BM, Hengel SM, Rock DA, Wienkers LC, Kunze KL. “Characterization of ritonavir-mediated inactivation of cytochrome P450 3A4.” Mol Pharmacol. 2014 Dec; 86(6):665-74. PubMed link.
  • Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N. “Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4.” Clin Pharmacol Ther. 2014 June; 95(6):653-62. PubMed link.
  • Zhang N, Seguin RP, Kunze KL, Zhang YY, Jeong H. “Characterization of inhibition kinetics of (S)-warfarin hydroxylation by noscapine: implications in warfarin therapy.” Drug Metab Dispos. 2013 Dec; 41(12):2114-23. PubMed link.
  • Lutz JD, VandenBrink BM, Babu KN, Nelson WL, Kunze KL, Isoherranen N. “Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple time-dependent inhibitor systems.” Drug Metab Dispos. 2013 Dec; 41(12):2056-65. PubMed link.
  • Fujioka Y, Kunze KL, Isoherranen N. “Risk assessment of mechanism-based inactivation in drug-drug interactions.” Drug Metab Dispos. 2012 Sep; 40(9):1653-7. PubMed link.
  • Peng CC, Shi W, Lutz JD, Kunze KL, Liu JO, Nelson WL, Isoherranen N. “Stereospecific metabolism of itraconazole by CYP3A4: dioxolane ring scission of azole antifungals.” Drug Metab Dispos. 2012 Mar; 40(3):426-35. PubMed link.
  • Fujioka Y, Kunze KL, Isoherranen N. “Risk assessment of mechanism-based inactivation in drug-drug interactions.” Drug Metab Dispos. 2012 Sep;40(9):1653-7. PubMed link.
  • Peng CC, Shi W, Lutz JD, Kunze KL, Liu JO, Nelson WL, Isoherranen N. “Stereospecific metabolism of itranconazole by CYP3A4: dioxolane ring scission of azole antifungals.” Drug Metab Dispos. 2012 Mar; 40(3):426-35. PubMed link.