title: Observations on hydrocodone and its metabolites in oral fluid specimens of the pain population: comparison with urine.
abstract: OBJECTIVE
  Hydrocodone undergoes metabolism via cytochrome P450 (CYP) 3A4 (N-demethylation) to norhydrocodone and via CYP2D6 (O-demethylation) to hydromorphone. Hydrocodone, hydromorphone, and norhydrocodone are excreted in urine and secreted in saliva. The goal was to characterize hydrocodone and its metabolites in oral fluid specimens of a pain population and compare to urine specimens.
  
  
  METHODS
  This retrospective analysis included more than 8,500 oral fluid specimens and more than 250,000 urine specimens collected between March and June 2012 that were sent to Millennium Laboratories (San Diego, CA) and analyzed for hydrocodone, hydromorphone, and norhydrocodone using liquid chromatography-tandem mass spectrometry. Statistical analyses and linear regressions were conducted using Microsoft Excel® 2010 and OriginPro v8.6.
  
  
  RESULTS
  The median oral fluid concentrations of hydrocodone and norhydrocodone were 122 and 7.7 ng/mL, respectively. However, the oral fluid concentrations of hydromorphone were below detection in many specimens (<1 ng/mL). The positive detection rate of parent drug and metabolites in oral fluid (17-31 percent detection rates) was much lower than in urine (63-75 percent detection rates). The geometric median metabolic ratio (MR) of norhydrocodone to hydrocodone was 0.07 in oral fluid and 1.2 in urine. The observed hydrocodone oral fluid concentrations were approximately 10-fold greater than previously reported plasma concentrations.
  
  
  CONCLUSIONS
  Oral fluid had a much lower norhydrocodone to hydrocodone MR compared to urine. Reference ranges for oral fluid drug concentrations should not be extrapolated from plasma ranges. The observed ranges of secreted hydrocodone and metabolite concentrations in oral fluid should help determine reference ranges for medication monitoring.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UC San Diego), La Jolla, California.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Cao
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UC San Diego), La Jolla, California; Doris A. Howell Palliative Care Service, San Diego, California.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ma
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UC San Diego), La Jolla, California; Diabetes Intense Medical Management Clinic, Veterans Affairs San Diego Healthcare System, La Jolla, California.
authors.forename: Candis M
authors.initials: CM
authors.lastname: Morello
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UC San Diego), La Jolla, California; Doris A. Howell Palliative Care Service, San Diego, California.
authors.forename: Rabia S
authors.initials: RS
authors.lastname: Atayee
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UC San Diego), La Jolla, California; UC San Diego Department of Pediatrics, Rady Children's Hospital, San Diego, California.
authors.forename: Brookie M
authors.initials: BM
authors.lastname: Best
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D016903:Drug Monitoring; D006801:Humans; D006853:Hydrocodone / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism* / Q000652:urine; D004091:Hydromorphone / Q000032:analysis / Q000652:urine; D010146:Pain / Q000188:drug therapy*; D012016:Reference Values; D012189:Retrospective Studies; D012463:Saliva / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C585150:norhydrocodone; D006853:Hydrocodone; D004091:Hydromorphone