title: Impact of methylation of acyl glucuronide metabolites on incurred sample reanalysis evaluation: ramiprilat case study.
abstract: BACKGROUND
  Reanalysis of incurred samples showed that the bioanalytical method for the quantification of ramipril and ramiprilat was generating irreproducible results for ramiprilat.
  
  
  RESULTS
  An additional peak interfering with ramiprilat was observed in the incurred samples but not in the calibrant and quality control samples. A similar interference was detected for ramipril, but it was chromatographically separated. Interferences were produced during sample preparation, which involves strong cation exchanger cartridges. The interfering products corresponded to the methylation of ramipril and ramiprilat glucuronide.
  
  
  CONCLUSIONS
  Following this discovery, a reproducible method was developed and successfully validated for ramipril and ramiprilat. Additional stability tests were performed in the presence of glucuronide and diketopiperazine metabolites of ramipril and ramiprilat to demonstrate the method specificity.
authors.affiliation: Algorithme Pharma Inc., 575 Armand-Frappier, Laval, Québec, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Côté
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lahaie
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bergeron
authors.forename: Catherine
authors.initials: C
authors.lastname: Dicaire
authors.forename: Natasha
authors.initials: N
authors.lastname: Savoie
authors.forename: Milton
authors.initials: M
authors.lastname: Furtado
authors.forename: Fabio
authors.initials: F
authors.lastname: Garofolo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood* / Q000627:therapeutic use; D016477:Artifacts; D002138:Calibration / Q000592:standards; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D002852:Chromatography, Ion Exchange; D054659:Diketopiperazines / Q000097:blood*; D020719:Glucuronides / Q000097:blood*; D017408:Guidelines as Topic; D006801:Humans; D013058:Mass Spectrometry; D008745:Methylation; D017257:Ramipril / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D012015:Reference Standards; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013048:Specimen Handling / Q000592:standards; D054928:Validation Studies as Topic
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D054659:Diketopiperazines; D020719:Glucuronides; C052549:ramiprilat; D017257:Ramipril