title: Rapid, biomimetic degradation in water of the persistent drug sertraline by TAML catalysts and hydrogen peroxide.
abstract: Iron TAML activators (oxidation catalysts based upon tetraamido macrocyclic ligands) at nanomolar concentrations in water activate hydrogen peroxide to rapidly degrade sertraline, the persistent, active pharmaceutical ingredient (API) in the widely used drug Zoloft. Although all the API is readily consumed, degradation slows significantly at one intermediate, sertraline ketone. The process occurs from neutral to basic pH. The pathway has been characterized through four early intermediates which reflect the metabolism of sertraline, providing further evidence that TAML activator/peroxide reactive intermediates mimic those of cytochrome P450 enzymes. TAML catalysts have been designed to exhibit considerable variability in reactivity and this provides an excellent tool for observing degradation intermediates of widely differing stabilities. Two elusive, hydrolytically sensitive intermediates and likely human metabolites, sertraline imine and N-desmethylsertraline imine, could be identified only by using a fast-acting catalyst. The more stable intermediates and known human metabolites, desmethylsertraline and sertraline ketone, were most easily detected and studied using a slow-acting catalyst. The resistance of sertraline ketone to aggressive TAML activator/peroxide treatment marks it as likely to be environmentally persistent and signals that its environmental effects are important components of the full implications of sertraline use.
authors.affiliation: Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Longzhu Q
authors.initials: LQ
authors.lastname: Shen
authors.forename: Evan S
authors.initials: ES
authors.lastname: Beach
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiang
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Tshudy
authors.forename: Natalya
authors.initials: N
authors.lastname: Khanina
authors.forename: Colin P
authors.initials: CP
authors.lastname: Horwitz
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bier
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Collins
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry; D032701:Biomimetics; D002384:Catalysis; D006861:Hydrogen Peroxide / Q000737:chemistry*; D058085:Iron Compounds / Q000737:chemistry*; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry*; D020280:Sertraline / Q000737:chemistry*; D014874:Water Pollutants, Chemical / Q000737:chemistry*; D018508:Water Purification / Q000379:methods*
chemical_list: D000928:Antidepressive Agents; D058085:Iron Compounds; D008024:Ligands; D047028:Macrocyclic Compounds; D014874:Water Pollutants, Chemical; D006861:Hydrogen Peroxide; D020280:Sertraline