Prescription Opioids. V. Metabolism and Excretion of Oxymorphone in Urine Following Controlled Single Dose Administration

Abstract

Oxymorphone (OM), a prescription opioid and metabolite of oxycodone, was included in the recently published proposed revisions to the Mandatory Guidelines for Federal Workplace Drug Testing Programs. To facilitate toxicological interpretation, this study characterized the time course of OM and its metabolite, noroxymorphone (NOM), in hydrolyzed and non-hydrolyzed urine specimens. Twelve healthy subjects were administered a single 10 mg controlled-release OM dose, followed by a periodic collection of pooled urine specimens for 54 h following administration. Analysis for free and total OM and NOM was conducted by liquid chromatography tandem mass spectrometry (LC-MS-MS), at a 50 ng/mL limit of quantitation (LOQ). Following enzymatic hydrolysis, OM and NOM were detected in 89.9% and 13.5% specimens, respectively. Without hydrolysis, OM was detected in 8.1% specimens, and NOM was not detected. The mean ratio of hydrolyzed OM to NOM was 41.6. OM was frequently detected in the first pooled collection 0-2 h post-dose, appearing at a mean of 2.4 h. NOM appeared at a mean of 8.3 h. The period of detection at the 50 ng/mL threshold averaged 50.7 h for OM and 11.0 h for NOM. These data support that OM analysis conducted using a 50 ng/mL threshold should include hydrolysis or optimize sensitivity for conjugated OM.

Identification of oxymorphone as decomposition product of the permitted drug methylnaltrexone

“…On the contrary, reference collection urine available in the laboratory, which was earlier tested positive for oxymorphone metabolites, contained significant amounts of oxymorphone glucuronide with lower amounts of noroxymorphone, noroxymorphone glucuronide, and oxymorphol. This is consistent with oxymorphone metabolism data available in the literature …”

“…This is consistent with oxymorphone metabolism data available in the literature. [10][11][12] Based on the foregoing, the testing authority was provided with the report that the athlete's sample is negative for oxymorphone.…”

Hydrocodone, Oxycodone, and Morphine Metabolism and Drug–Drug Interactions

“…Metabolic enzymes are divided into phase I and phase II metabolism, with the cytochrome P450 enzymes (CYP) the major superfamily within the phase I metabolic enzymes and the UDP-glucuronosyltransferases (UGT) the major phase II enzyme superfamily. Most opioids are metabolized by both the CYP and UGT family of enzymes ( Trescot et al, 2008 ), with several, including codeine, hydrocodone, oxycodone, tramadol, and morphine, metabolized primarily by CYP3A4, CYP2D6 and UGT2B7 ( Cone et al, 1978 ; Yue et al, 1991a , b ; Otton et al, 1993 ; Pöyhiä et al, 1993 ; Hagen et al, 1995 ; Caraco et al, 1996a , b ; Coffman et al, 1997 ; Paar et al, 1997 ; Coffman et al, 1998 ; Green et al, 1998 ; Subrahmanyam et al, 2001 ; Donnelly et al, 2002 ; Shapiro and Shear, 2002 ; Zheng et al, 2002 ; Stone et al, 2003 ; Benetton et al, 2004 ; Hutchinson et al, 2004 ; Lalovic et al, 2004 ; Zheng et al, 2004 ; Baldacci and Thormann, 2006 ; Lalovic et al, 2006 ; Madadi and Koren, 2008 ; Ohno et al, 2008 ; Jenkins et al, 2009 ; Nieminen et al, 2009 ; Cone et al, 2013a , b ; Barakat et al, 2014 ; Elder et al, 2014 ; Kurogi et al, 2014 ; DePriest et al, 2016a , b ; Romand et al, 2017 ; Shen et al, 2019 ). Approximately 25% and 50% of all pharmaceutical drugs are substrates of CYP2D6 and CYP3A4, respectively ( Bertz and Granneman, 1997 ; Evans and Relling, 1999 ; Ingelman-Sundberg, 2005 ; Ingelman-Sundberg and Rodriguez-Antona, 2005 ; Trescot et al, 2008 ; Zhou, 2009 ; Zanger and Schwab, 2013 ), while UGT2B7 is a major UGT isoform that is responsible for catalyzing the biotransformation of numerous xenobiotics and endogenous substances ( Bhasker et al, 2000 ; Tukey and Strassburg, 2000 ; Stingl et al, 2014 ; Shen et al, 2019 ).…”