title: The kinetic mechanism for cytochrome P450 metabolism of type II binding compounds: evidence supporting direct reduction.
abstract: The metabolic stability of a drug is an important property that should be optimized during drug design and development. Nitrogen incorporation is hypothesized to increase the stability by coordination of nitrogen to the heme iron of cytochrome P450, a binding mode that is referred to as type II binding. However, we noticed that the type II binding compound 1 has less metabolic stability at sub-saturating conditions than a closely related type I binding compound 3. Three kinetic models will be presented for type II binder metabolism; (1) Dead-end type II binding, (2) a rapid equilibrium between type I and II binding modes before reduction, and (3) a direct reduction of the type II coordinated heme. Data will be presented on reduction rates of iron, the off rates of substrate (using surface plasmon resonance) and the catalytic rate constants. These data argue against the dead-end, and rapid equilibrium models, leaving the direct reduction kinetic mechanism for metabolism of the type II binding compound 1.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, WA 98119, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Pearson
authors.forename: Upendra P
authors.initials: UP
authors.lastname: Dahal
authors.forename: Daniel
authors.initials: D
authors.lastname: Rock
authors.forename: Chi-Chi
authors.initials: CC
authors.lastname: Peng
authors.forename: James O
authors.initials: JO
authors.lastname: Schenk
authors.forename: Carolyn
authors.initials: C
authors.lastname: Joswig-Jones
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Jones
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004355:Drug Stability; D006418:Heme / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000737:chemistry; D007700:Kinetics; D008954:Models, Biological; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance; D053719:Tandem Mass Spectrometry
chemical_list: D011804:Quinolines; D011994:Recombinant Proteins; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009584:Nitrogen