RESUMEN
Oxycodone is a widely prescribed, full agonist opioid analgesic. As such, it is used clinically to treat different kinds of painful conditions, with a relatively high potential for doping practices in athletes. In this paper, different classic and innovative miniaturised matrices from blood and urine have been studied and compared, to evaluate their relative merits and drawbacks within therapeutic drug monitoring (TDM) and to implement new protocols for anti-doping analysis. Plasma, dried blood spots (DBS) and dried plasma spots (DPS) have been studied for TDM purposes, while urine, dried urine spots (DUS) and volumetric absorptive microsamples (VAMS) from urine for anti-doping. These sampling techniques were coupled to an original bioanalytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the evaluation and monitoring of the levels of oxycodone and its major metabolites (noroxycodone and oxymorphone) in patients under pain management and in athletes. The method was validated according to international guidelines, with good results in terms of precision, extraction yield and accuracy for all considered micromatrices. Thus, the proposed sampling, pre-treatment and analysis are attractive strategies for oxycodone determination in human blood and urine, with advanced options for application to derived micromatrices. Microsampling procedures have significant advantages over classic biological matrices like simplified sampling, storage and processing, but also in terms of precision (<9.0% for DBS, <7.7% for DPS, <7.1% for DUS, <5.3% for VAMS) and accuracy (>73% for DBS, >78% for DPS, >74% for DUS, >78% for VAMS). As regards extraction yield, traditional and miniaturised sampling approaches are comparable (>67% for DBS, >74% for DPS, >75% for DUS, >75% for VAMS). All dried matrices have very low volumes, leading to a significant advantage in terms of analysis feasibility. On the other hand, this also leads to a corresponding decrease in the overall sensitivity.
Asunto(s)
Morfinanos/sangre , Morfinanos/orina , Oxicodona/sangre , Oxicodona/orina , Oximorfona/sangre , Oximorfona/orina , Recolección de Muestras de Sangre , Líquidos Corporales/química , Cromatografía Liquida/métodos , Doping en los Deportes/métodos , Pruebas con Sangre Seca/métodos , Monitoreo de Drogas/métodos , Humanos , Miniaturización/métodos , Plasma/química , Manejo de Especímenes/métodos , Espectrometría de Masas en Tándem/métodos , Orina/químicaAsunto(s)
Naltrexona/análogos & derivados , Antagonistas de Narcóticos/orina , Narcóticos/orina , Oximorfona/orina , Detección de Abuso de Sustancias/métodos , Doping en los Deportes , Estabilidad de Medicamentos , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Naltrexona/química , Naltrexona/orina , Antagonistas de Narcóticos/química , Narcóticos/análisis , Oximorfona/análisis , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/orinaRESUMEN
BACKGROUND: Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone. METHODS: Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI). RESULTS: Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study. CONCLUSIONS: Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment.
Asunto(s)
Morfinanos/sangre , Morfinanos/orina , Oxicodona/sangre , Oxicodona/orina , Oximorfona/sangre , Oximorfona/orina , Espectrometría de Masas en Tándem , Anciano , Anciano de 80 o más Años , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morfinanos/metabolismo , Oxicodona/metabolismo , Oximorfona/metabolismoRESUMEN
BACKGROUND: We evaluated the analytical performance of the DRI hydrocodone/hydromorphone assay by comparing semiquantitative values obtained by this assay with values obtained by a liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) method. We also evaluated the possibility of lowering the cutoff of the DRI assay from 300 to 100 ng/mL. METHODS: We compared semiquantitative values obtained by the DRI assay in 97 specimens with values obtained by the LC-MS/MS method including 10 specimens containing hydrocodone and/or hydromorphone concentrations between 105.0 and 145.0 ng/mL (determined by LC-MS/MS) to determine the sensitivity at 100 ng/mL. In addition, several opioids at a concentration of 5000 ng/mL were also analyzed by the DRI assay to determine its specificity. RESULTS: We observed no false-negative result using the DRI immunoassay in 96 specimens that showed semiquantitative values at 100 ng/mL or higher. However, one specimen containing 110 ng/mL of hydrocodone was false negative with the DRI assay (semiquantitative value 88 ng/mL, below 100 ng/mL cutoff). The semiquantitative values produced by DRI showed poor correlation with values determined by the LC-MS/MS method. The sensitivity of the DRI assay at 100 ng/mL was 90%, and the assay was very specific showing minimal cross-reactivity only with oxycodone and oxymorphone. CONCLUSIONS: DRI immunoassay for hydrocodone/hydromorphone is a cost-effective method of screening urine specimens in the clinical environment at a lower cutoff of 100 ng/mL.
Asunto(s)
Hidrocodona/orina , Hidromorfona/orina , Analgésicos Opioides/orina , Cromatografía Liquida/métodos , Humanos , Inmunoensayo/métodos , Oxicodona/orina , Oximorfona/orina , Sensibilidad y Especificidad , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
Drug monitoring laboratories utilize a hydrolysis process to liberate the opiates from their glucuronide conjugates to facilitate their detection by tandem mass spectrometry (MS). Both acid and enzyme hydrolysis have been reported as viable methods, with the former as a more effective process for recovering codeine-6-glucuronide and morphine-6-glucuronide. Here, we report concerns with acid-catalyzed hydrolysis of opioids, including a significant loss of analytes and conversions of oxycodone to oxymorphone, hydrocodone to hydromorphone and codeine to morphine. The acid-catalyzed reaction was monitored in neat water and patient urine samples by liquid chromatography-time-of-flight and tandem MS. These side reactions with acid hydrolysis may limit accurate quantitation due to loss of analytes, possibly lead to false positives, and poorly correlate with pharmacogenetic profiles, as cytochrome P450 enzyme (CYP2D6) is often involved with oxycodone to oxymorphone, hydrocodone to hydromorphone and codeine to morphine conversions. Enzymatic hydrolysis process using the purified, genetically engineered ß-glucuronidase (IMCSzyme®) addresses many of these concerns and demonstrates accurate quantitation and high recoveries for oxycodone, hydrocodone, oxymorphone and hydromorphone.
Asunto(s)
Analgésicos Opioides/orina , Alcaloides Opiáceos/orina , Cromatografía Liquida , Codeína/análogos & derivados , Codeína/orina , Citocromo P-450 CYP2D6/metabolismo , Glucuronidasa/metabolismo , Humanos , Hidrocodona/orina , Hidrólisis , Hidromorfona/orina , Morfina/orina , Derivados de la Morfina/orina , Oxicodona/orina , Oximorfona/orina , Manejo de Especímenes , Espectrometría de Masas en TándemRESUMEN
It is reasonable to expect the presence of multiple drugs to present a complicated picture of toxicity. We report a fatal case involving a young man who purchased illicit drugs and knowingly consumed them. After consuming these drugs and going to sleep in his friend's car, he was found unresponsive the next morning with no signs of physical violence. Drugs found in the peripheral blood at autopsy were oxymorphone, methylone and ethanol at concentrations of 0.106, 0.50 and 130 mg/dL, respectively. The levels of oxymorphone and methylone in peripheral blood were comparable to those observed in other reported fatalities. Cocaine and benzoylecgonine were detected in the urine but not in the blood. Measureable concentrations were also observed for oxymorphone and methylone in urine, liver, kidney and bile. The physical findings at autopsy included pulmonary edema. This is the only reported fatal case involving this combination of drugs encountered in our laboratory.
Asunto(s)
Sobredosis de Droga/diagnóstico , Etanol/metabolismo , Metanfetamina/análogos & derivados , Oximorfona/metabolismo , Adulto , Etanol/sangre , Etanol/orina , Resultado Fatal , Toxicología Forense , Humanos , Masculino , Metanfetamina/sangre , Metanfetamina/metabolismo , Metanfetamina/orina , Oximorfona/sangre , Oximorfona/orina , Edema Pulmonar/diagnósticoRESUMEN
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.
Asunto(s)
Analgésicos Opioides/orina , Oximorfona/orina , Detección de Abuso de Sustancias/métodos , Adulto , Analgésicos Opioides/administración & dosificación , Cromatografía Líquida de Alta Presión , Creatinina/orina , Preparaciones de Acción Retardada/administración & dosificación , Femenino , Humanos , Masculino , Morfinanos/orina , Oxicodona/orina , Oximorfona/administración & dosificación , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
Continuing our previous studies analyzing drugs of abuse in municipal wastewater, a method was developed for the analysis of opiates in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). Eight opiate drugs and metabolites were analyzed including codeine, hydrocodone, hydromorphone, 6-monoacetylmorphine (6-MAM, the primary urinary metabolite of heroin), morphine, norhydrocodone (the primary urinary metabolite of hydrocodone), oxycodone and oxymorphone. These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Waste Water Treatment Plant in Oxford, Mississippi (MS) and the University Wastewater Treatment Plant in University, MS. These wastewater samples were collected on weekends in which the Ole Miss Rebel football team held home games (Vaught-Hemingway Stadium, University, MS 38677). The collected samples were analyzed using a validated method and found to contain codeine, hydrocodone, hydromorphone, morphine, norhydrocodone, oxycodone and oxymorphone. None of the samples contained 6-MAM.
Asunto(s)
Analgésicos Opioides/análisis , Alcaloides Opiáceos/análisis , Detección de Abuso de Sustancias/métodos , Aguas Residuales/química , Contaminantes Químicos del Agua/análisis , Analgésicos Opioides/orina , Cromatografía Liquida , Codeína/orina , Fútbol Americano , Humanos , Hidrocodona/orina , Hidromorfona/orina , Morfina/orina , Alcaloides Opiáceos/orina , Oxicodona/orina , Oximorfona/orina , Espectrometría de Masas en Tándem , Aguas Residuales/análisisRESUMEN
This article examines the US Army's Medical Review Officer (MRO) drug positive urinalysis evaluations from 2009 through 2012. We retrospectively analyzed nearly 70,000 MRO results by year, drug and Army component. Of the MRO reviewable positive results, the Army's unauthorized drug positive rate was 22.21%. The component rates were 20.81, 24.17 and 26.09% for the Active Duty, Reserve and National Guard, respectively. By drug, the average unauthorized rates over these 4 years were 13.78% for oxycodone, 24.62% oxymorphone, 18.56% d-amphetamine, 98.04% d-methamphetamine, 21.97% codeine, 45.21% morphine and 100% steroids. In 2012 testing began for hydrocodone and hydromorphone and their unauthorized rates were 12.32 and 15.04%, respectively. The Army's unauthorized drug positive rate peaked in 2012 when it increased over 44% from the previous year. The 2012 rates in decreasing order were steroids > D-methamphetamine > morphine > oxymorphone > oxycodone > codeine > D-amphetamine > hydromorphone > hydrocodone. This comprehensive analysis showed that the majority of the Army's MRO reviews were associated with the use of authorized prescriptions; however, there appears to be significant abuse of oxycodone and D-amphetamine.
Asunto(s)
Personal Militar , Detección de Abuso de Sustancias/métodos , Trastornos Relacionados con Sustancias/diagnóstico , Anfetamina/orina , Codeína/orina , Humanos , Hidrocodona/orina , Hidromorfona/orina , Metanfetamina/orina , Morfina/orina , Oxicodona/orina , Oximorfona/orina , Estudios Retrospectivos , Estados Unidos , UrinálisisRESUMEN
OBJECTIVE: Saliva is purported to have a close correspondence to plasma concentrations due to a passive diffusion process from plasma to saliva. However, limited data are available characterizing oxycodone and its metabolites in saliva. The purpose of this analysis was to evaluate the use of saliva monitoring in patients prescribed oxycodone and to compare the disposition of oxycodone in saliva and urine. DESIGN: This retrospective analysis examined deidentified urine and saliva specimens collected from patients with chronic pain. These specimens were received at Millennium Laboratories between March and June 2012 and analyzed using LCMS/MS to quantitate oxycodone, noroxycodone, and oxymorphone concentrations. RESULTS: The geometric mean metabolic ratio (MR) of noroxycodone to oxycodone in saliva was 0.11, whereas the geometric mean MR in urine was 1.7. The geometric mean oxycodone concentration in saliva was 860 ng/mL (range, 1.5-8,600,000 ng/mL; 95% CI, 770-950 ng/mL), whereas the geometric mean noroxycodone concentration was 98 ng/mL (range, 2.3-8,800 ng/mL; 95% CI, 90-107 ng/mL). Fifty-four of the saliva specimens (6 percent) had oxycodone concentrations between 10,000 and 9,000,000 ng/mL. CONCLUSIONS: Oxycodone is predominant over noroxycodone in saliva (similar to plasma), while the reverse relationship exists in urine. Much greater oxycodone concentrations were found in saliva than are expected in plasma (up to a 1,000-fold difference). Saliva concentrations are lower than urine concentrations but still may not reflect plasma disposition. Possible explanations include medication residue in the mouth (recent medication use or misuse) or active secretion into saliva. Saliva analysis may be used for qualitative drug monitoring of oxycodone, with detection rates similar to urine; however, further characterization is needed for appropriate interpretation.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Monitoreo de Drogas , Morfinanos/orina , Oxicodona/uso terapéutico , Oximorfona/orina , Saliva/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Oxicodona/metabolismo , Estudios Retrospectivos , SalivaciónRESUMEN
Oxycodone is an opioid analgesic metabolized to oxymorphone and noroxycodone by cytochrome P450 (CYP) 2D6 and 3A4/5, respectively. This was a retrospective study to evaluate sex, age, urinary pH and concurrent medication use on oxycodone, oxymorphone and noroxycodone distributions. Urine specimens obtained from patients on chronic opioid therapy were analyzed by LC-MS-MS. There were 108,923 specimens from a subject's first or single visit, who were at least 18 years of age, and had documented physician-reported oxycodone use. The majority of specimens had detectable oxycodone urine concentrations (n = 106,852) resulting in oxycodone mole fractions (arithmetic mean ± SD) of 0.44 ± 0.27. Ninety-eight percent (n = 106,229) and 49% (n = 53,394) had detectable oxymorphone and noroxycodone, respectively. Oxycodone and oxymorphone mole fractions were lower in women compared with men (P < 0.0001). Mean ± SD age was 49.1 ± 12.9 years. Noroxycodone mole fractions were highest in the 65 years and older age group. Concurrent use of a CYP2D6 inhibitor, but not a CYP3A4/5 inhibitor, altered oxycodone and oxymorphone mole fractions. Dual inhibition of CYP2D6 and CYP3A4/5 did not result in a statistical difference upon comparison with CYP2D6 inhibitor or CYP3A4/5 inhibitor use. Patient factors affect oxycodone and metabolite mole fractions and suggest increased awareness of each contribution when attempting to monitor therapy with urine drug testing.
Asunto(s)
Analgésicos Opioides/orina , Morfinanos/orina , Oxicodona/orina , Oximorfona/orina , Dolor/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Anciano , Analgésicos Opioides/administración & dosificación , Cromatografía Liquida , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Morfinanos/administración & dosificación , Oxicodona/administración & dosificación , Oximorfona/administración & dosificación , Dolor/orina , Estudios Retrospectivos , Factores Sexuales , Manejo de Especímenes , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
The opioid analgesic oxycodone is widely abused and increasingly associated with overdose deaths. A sensitive analytical method was developed for oxycodone and its metabolites, noroxycodone and oxymorphone, in human plasma, urine (±enzymatic hydrolysis at 50°C for 16 h) and liver microsomes (HLMs). Liquid-liquid extraction was followed by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. The calibration range was 0.2-250 ng/mL for plasma and HLM and 10-5000 ng/mL for urine. Intra- and interrun accuracies were within 13.3% of target; precisions were within 12.8% for all matrices. Recoveries from plasma were: oxycodone, 75.6%; noroxycodone, 37.4% and oxymorphone, 18.2%. Analytes exhibited room temperature stability in plasma and urine up to 24 h, and freeze-thaw stability in plasma up to three cycles. In 24-h hydrolyzed urine from subjects administered intranasal oxycodone (30 mg/70 kg, n = 5), mean concentrations (ng/mL) and % daily doses excreted were: oxycodone, 1150, 6.53%; noroxycodone, 1330, 7.81% and oxymorphone, 3000, 17.1%. Oxycodone incubated with HLM produced more noroxycodone than oxymorphone. With a panel of recombinant human cytochrome P450s (CYPs), CYP2C18 and CYP3A4 produced the most noroxycodone, whereas CYP2D6 produced the most oxymorphone. These results demonstrate a new method suitable for both in vivo and in vitro metabolism and pharmacokinetic studies of oxycodone.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Morfinanos/sangre , Oxicodona/sangre , Oximorfona/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Analgésicos Opioides/sangre , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Humanos , Extracción Líquido-Líquido , Microsomas Hepáticos/química , Morfinanos/orina , Oxicodona/orina , Oximorfona/orina , Control de Calidad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Manejo de Especímenes , Espectrometría de Masas en TándemRESUMEN
A presumed hook effect in the semiquantitative DRI Oxycodone immunoassay, OXY3S (Cobas Integra, Roche Diagnostics), was investigated in 14 urine samples with gas chromatography/mass spectrometry (GC-MS) >10,000 ng/mL but OXY3S <1,000 ng/mL. These samples included the index case, a false-negative OXY3S result with >75,000 ng/mL oxycodone + oxymorphone by GC-MS confirmation. Patient samples needed 2- to 16-fold dilution to obtain the correct OXY3S response. The OXY3S test did not hook at high-spiked concentrations of oxycodone, oxymorphone or oxymorphone-3ß-d-glucuronide in drug-free urine. The OXY3S test parameters were replicated in a development channel on the Cobas using DRI Reagents (Microgenics, CA, USA) and were subsequently modified. Delayed sample addition or doubling of Reagent 1 (R1: antibody/substrate/co-factor) yielded maximal immunoassay response (>10,000 ng/mL) in 12 of 14 and 14 of 14 undiluted patient samples, respectively. Supplementation of R1 with substrate alone did not correctly recover oxycodone from any of the samples, while co-factor supplementation resulted a maximal OXY3S response in 13 of 14 samples. The remaining (index) sample could only be corrected by supplemental R1. The semiquantitative utility of the DRI Oxycodone assay is questionable. Although the precise cause of the under-recovery could not be determined, the modification presented permits reliable oxycodone determination at the high concentrations frequently seen in clinical urine samples.
Asunto(s)
Inmunoensayo/métodos , Oxicodona/orina , Adulto , Anciano , Femenino , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Masculino , Persona de Mediana Edad , Oximorfona/orina , Manejo de Especímenes , Detección de Abuso de Sustancias/métodosRESUMEN
The ongoing epidemic of prescription opioid abuse in the United States has prompted interest in semi-synthetic opioids in the federal workplace drug testing program. This study characterized the metabolism and disposition of oxycodone (OC) in human urine. Twelve healthy adults were administered a single oral 20 mg dose of OC in a controlled clinical setting. Urine specimens were collected at timed intervals up to 52 h and analyzed by liquid chromatography-tandem mass spectrometry (limit of quantitation: 50 ng/mL) for OC, oxymorphone (OM), noroxycodone (NOC) and noroxymorphone (NOM) with and without enzymatic hydrolysis. OC and NOC appeared in urine within 2 h, followed by OM and NOM. Peak concentrations of OC and metabolites occurred between 3 and 19 h. Mean peak concentrations in hydrolyzed urine were in the following order: NOC > OC > OM > NOM. Only OM appeared to be excreted extensively as a conjugated metabolite. OC concentrations declined more quickly than NOC and OM. At a cutoff concentration of 50 ng/mL, detection times were approximately 30 h for OC and 40 h for NOC and OM. Some specimens did not contain OC, but most contained NOC, thereby facilitating interpretation that OC was the administered drug; however, five specimens contained only OM. These data provide information that should facilitate the selection of appropriate test parameters for OC in urine and assist in the interpretation of test results.
Asunto(s)
Analgésicos Opioides/farmacocinética , Oxicodona/farmacocinética , Detección de Abuso de Sustancias/métodos , Adulto , Analgésicos Opioides/orina , Cromatografía Líquida de Alta Presión , Empleo , Femenino , Humanos , Masculino , Morfinanos/orina , Oxicodona/orina , Oximorfona/orina , Espectrometría de Masas en Tándem , Factores de Tiempo , Lugar de Trabajo , Adulto JovenRESUMEN
The object of this study was to evaluate the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and Feb 2010. The observed excretion was modeled using logarithmic transformation and approximated a Gaussian distribution. Oxycodone excretion into urine had a geometric mean of 1.93 mg/g of creatinine and oxymorphone had a value of 0.41 mg/g of creatinine. Increasing concentrations of oxycodone correlated with a smaller proportion of oxymorphone excretion suggesting saturation of oxycodone metabolism. Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 ± 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 ± 1.1%) in the population. Samples with concentrations of oxycodone above 10 mg/g of creatinine showed a sub-population of subjects with metabolic ratios roughly 100-fold less than the linear predictive model in this study. This study describes typical ranges for oxycodone and oxymorphone in urine, and showed that it is possible to identify fast or slow metabolizers who may be at risk for adverse events.
Asunto(s)
Analgésicos Opioides/orina , Oxicodona/orina , Oximorfona/orina , Dolor/orina , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapéutico , Cromatografía Líquida de Alta Presión , Humanos , Modelos Biológicos , Oxicodona/farmacocinética , Oxicodona/uso terapéutico , Dolor/tratamiento farmacológico , Valores de Referencia , Reproducibilidad de los Resultados , Estudios Retrospectivos , Espectrometría de Masas en Tándem , Factores de TiempoRESUMEN
BACKGROUND: In clinical laboratories, a large proportion of the toxicology workload is drug confirmations. Our GC-MS method for opioid confirmation detects total codeine, morphine, hydrocodone, hydromorphone, oxycodone and oxymorphone. The objective of this study was to develop a LC-MS/MS assay measuring the above drugs and glucuronide metabolites. In addition, to determine if measuring free drug only would lead to false negative results. RESULTS: In 85 patient urines, 43% were positive for morphine glucuronide, but not morphine, 48% were positive for hydromorphone glucuronide, but not hydromorphone, 33% were positive for codeine glucuronide, but not codeine, and 44% were positive for oxymorphone glucuronide, but not oxymorphone. CONCLUSION: We developed an LC-MS/MS assay capable of detecting codeine, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone and glucuronide metabolites. Detection of free drug only led to false negative confirmations.