57464-82-1

Upstream product

• 2784-27-2 5-(4-hydroxyphenyl)-5-phenylhydantoin 
• 17816-50-1 5-(4-methoxyphenyl)-5-phenylimidazolidine-2,4-dione 
• 1137-42-4 4-Hydroxybenzophenone 
• 151-50-8 potassium cyanide 
• 1066-33-7 ammonium bicarbonate 
• 57-41-0 phenythoin 
• 506-87-6 ammonium carbonate 

Relevant academic research and scientific papers

Deracemization of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH): Practical synthesis of (-)-(S)-HPPH

In the presence of 10% NaOH in boiling MeOH enantiomerically enriched HPPH is racemized. This permits the deracemization of HPPH in the presence of brucine, giving enantiomerically pure (-)-(S)-HPPH [(-)-(S)-5-(4-hydroxyphenyl)- 5-phenylhydandoin].

Metabolism of Phenytoin and Covalent Binding of Reactive Intermediates in Activated Human Neutrophils

Activation of neutrophils by phorbol-12-myristate-13-acetate (PMA) causes rapid production of superoxide radical (O2-), leading to the formation of additional reactive oxygen species, including hydrogen peroxide (H2O2), hypochlorous acid (HOCl), and possibly hydroxyl radical (*OH). These reactive oxygen species have been associated with the oxidation of some drugs. We investigated the metabolism of phenytoin (5,5-diphenylhydantoin) and the covalent binding of reactive intermediates to cellular macromolecules in activated neutrophils. In incubations with 100 μM phenytoin, PMA-stimulated neutrophils from six human subjects produced p-, m-, and o-isomers of 5-(hydroxyphenyl)-5-phenylhydantoin (HPPH) in a ratio of 1.0: 2.1:2.8, respectively, as well as unidentified polar products. Analysis of cell pellets demonstrated that phenytoin was bioactivated to reactive intermediates that bound irreversibly to macromolecules in neutrophils. Glutathione, catalase, superoxide dismutase, azide, and indomethacin all diminished the metabolism of phenytoin and the covalent binding of its reactive intermediates. The iron-inactivating chelators desferrioxamine and diethylenetriaminepentaacetic acid had little or no effect on the metabolism of phenytoin by neutrophils, demonstrating that adventitious iron was not contributing via Fenton chemistry. In an *OH-generating system containing H2O2 and Fe2+ chelated with ADP, phenytoin was oxidized rapidly to unidentified polar products and to p-, m-, and o-HPPH (ratio 1.0:1.7:1.5, respectively). Reagent HOCl and human myeloperoxidase (MPO), in the presence of Cl- and H2O2, both formed the reactive dichlorophenytoin but no HPPH. However, no chlorinated phenytoin was detected in activated neutrophils, possibly because of its high reactivity. These findings, which demonstrated that activated neutrophils biotransform phenytoin in vitro to hydroxylated products and reactive intermediates that bind irreversibly to tissue macromolecules, are consistent with phenytoin hydroxylation by *OH generated by a transition metal-independent process, chlorination by HOCl generated by MPO, and possibly cooxidation by neutrophil hydroperoxidases. Neutrophils activated in vivo may similarly convert phenytoin to reactive intermediates, which could contribute to some of the previously unexplained adverse effects of the drug.

Stable-isotope methodology for the bioavailability study of phenytoin during multiple-dosing regimens

With the highly sensitive and specific gas chromatography-mass spectrometry (GC-MS), plasma concentrations resulting from an intravenous administration of only a small amount of stable isotopically labeled phenytoin (DPH-d10) were determined to obtain information on the accurate clearance values under steady-state conditions attained with unlabeled phenytoin (DPH-d0). A time course of DPH-d10 concentrations was followed simultaneously with DPH-d0 during dosing intervals by GC-MS, with DPH-d5 as an internal standard. The present stable-isotope methodology offered advantages for the estimation of absolute bioavailability of the oral phenytoin dose in patients, while normal therapy was continued and not withdrawn.