title: Ponalrestat does not cause a protein binding interaction with warfarin in diabetic patients.
abstract: Ponalrestat (Statil, ICI; Prodiax, Merck Sharp and Dohme) is an aldose reductase inhibitor which is highly protein bound. Ponalrestat markedly displaced warfarin from its protein binding in vitro at a concentration of 500 micrograms ml-1, but not at a concentration of 50 or 100 micrograms ml-1. Twelve diabetic patients (six males), age range 38-65 years, in receipt of chronic stable warfarin therapy, were given ponalrestat (600 mg daily) for 2 weeks in an open trial. A matching placebo tablet was administered for 1 week before and after the active treatment period. Patients were seen ten times (four times during the ponalrestat phase), and during the ponalrestat phase, plasma samples were also taken before and at 3 h after the daily dose of ponalrestat. At none of the visits was there any significant change in prothrombin ratio (INR), plasma total or unbound warfarin concentrations, or percentage protein binding of warfarin. No clinical complications of combination treatment were detected. The maximum ponalrestat concentration observed in the patients was approximately 100 micrograms ml-1. We conclude that no significant interaction between these drugs occurs at the doses of ponalrestat studied.
authors.affiliation: Department of Clinical Pharmacology, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: R F
authors.initials: RF
authors.lastname: Moulds
authors.forename: R O
authors.initials: RO
authors.lastname: Fullinfaw
authors.forename: R W
authors.initials: RW
authors.lastname: Bury
authors.forename: W E
authors.initials: WE
authors.lastname: Plehwe
authors.forename: N
authors.initials: N
authors.lastname: Jacka
authors.forename: K M
authors.initials: KM
authors.lastname: McGrath
authors.forename: F I
authors.initials: FI
authors.lastname: Martin
mesh_terms: D000328:Adult; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003920:Diabetes Mellitus / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010793:Phthalazines / Q000097:blood* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D014859:Warfarin / Q000097:blood*
chemical_list: D001798:Blood Proteins; D007004:Hypoglycemic Agents; D010793:Phthalazines; C042829:ponalrestat; D014859:Warfarin; D000449:Aldehyde Reductase