An automated, highly sensitive LC-MS/MS assay for the quantification of the opiate antagonist naltrexone and its major metabolite 6β-naltrexol in dog and human plasma

Clavijo, Claudia F.; Bendrick-Peart, Jamie; Zhang, Yan Ling; Johnson, Gillian; Gasparic, Antje; Christians, Uwe

doi:10.1016/j.jchromb.2008.08.021

Cited by 20 publications

(13 citation statements)

References 17 publications

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“…Legal guardian consent was obtained for all patients, and children's assent was obtained. Arterial blood samples for methadone assay were obtained at 0, 5, 10, 15, 20, and 40 min as well as 1,2,4,5,6,8,10,12,24, and 48 h. Gas chromatography-mass spectrometry was used for assay. The limit of quantitation was determined to be 10 mcgÁl À1 , and the upper end of the linear range is 3000 mcgÁl À1 .…”

Section: Study 1 (University Of Virginia; Nct 01205256)mentioning

confidence: 99%

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

Ward

Drover

Hammer

et al. 2014

Pediatric Anesthesia

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Background The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg.L−1, while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg.L−1. The racemate of methadone which is commonly used in pediatric and anaesthetic care is metabolized to EDDP (2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine) and EMDP (2-ethyl-5-methyl-3,3-diphenylpyrroline). Methods Data from 4 studies (age 33 weeks PMA-15 years) were pooled (n=56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70 kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n=7) allowed further study of R and S enantiomer pharmacokinetics. Results A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between subject variability) were central volume (V1) 21.5 (29%) L.70kg−1, peripheral volumes of distribution V2 75.1 (23%) L.70kg−1, V3 484 (8%) L.70kg−1, clearance (CL) 9.45 (11%) L.h−1.70kg−1 and inter-compartment clearances Q2 325 (21%) L.h−1.70kg−1, Q3 136 (14%) L.h−1.70kg−1. EDDP formation clearance was 9.1 (11%) L.h−1.70kg−1, formation clearance of EMDP from EDDP 7.4 (63%) L.h−1.70kg−1, elimination clearance of EDDP was 40.9 (26%) L.h−1.70kg−1, and the rate constant for intermediate compartments 2.17 (43%) /h. Conclusions Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg.kg−1 per 8 h in neonates achieves a target concentration of 0.06 mg.L−1 within 36 h. Infusion, rather than intermittent dosing should be considered if this target is to be achieved in older children after cardiac surgery.

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Section: Study 1 (University Of Virginia; Nct 01205256)mentioning

confidence: 99%

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

Ward

Drover

Hammer

et al. 2014

Pediatric Anesthesia

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“…During recent years, on-line sample preparation has experienced a revival due to the increased use of mass spectrometers as HPLC detectors and their superior specificity and selectivity compared with UV detectors. LC-MS/MS including online enrichment has successfully been used by our laboratory (Christians et al ., 2000; Zhang et al ., 2005; Clavijo et al ., 2008). In our experience including the present assay, online extract has the following advantages: (A) it eliminates the need for external column extraction or evaporation steps; (B) it avoids the necessity for multiple manual steps with their potential for reducing precision and the occurrence of random errors; (C) it allows for the combination of large injection volumes without having negative effects on analytical column performance and life span; (D) it further removes salts and other compounds potentially causing ion suppression; (E) backflush allows for a ‘volume-less’ injection with sharper peaks improving separation and reproducibility of integration; and (F) the extraction of each individual sample is recorded by the regulatory compliant software, which is an advantage in a good laboratory practice (GLP) environment.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a sensitive assay for the quantification of imatinib using LC/LC‐MS/MS in human whole blood and cell culture

Klawitter

Zhang

Klawitter

et al. 2009

Biomedical Chromatography

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We developed and validated a semi-automated LC/LC-MS/MS assay for the quantification of imatinib in human whole blood and leukemia cells. After protein precipitation, samples were injected into the HPLC system and trapped onto the enrichment column (flow 5 mL/min); extracts were back-flushed onto the analytical column. Ion transitions [M + H]+ of imatinib (m/z = 494.3 → 394.3) and its internal standard trazodone (372.5 → 176.3) were monitored. The range of reliable response was 0.03–75 ng/mL. The inter-day precisions were: 8.4% (0.03 ng/mL), 7.2% (0.1 ng/mL), 6.5% (1 ng/mL), 8.2% (10 ng/mL) and 4.3% (75 ng/mL) with no interference from ion suppression. Autosampler stability was 24 hs and samples were stable over three freeze–thaw cycles. This semi-automated method is simple with only one manual step, uses a commercially available internal standard, and has proven to be robust in larger studies.

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“…Naltrexone (NALT) is a competitive opioid antagonist that blocks the pharmacologic effect of heroin, morphine and other opioids. NALT also undergoes a significant first-pass metabolism [8,9].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a bioanalytical method for the simultaneous determination of heroin, its main metabolites, naloxone and naltrexone by LC–MS/MS in human plasma samples: Application to a clinical trial of oral administration of a heroin/naloxone formulation

Moreno-Vicente

Fernández-Nieva

Navarro

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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A bioanalytical method using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification of heroin, its main metabolites and naloxone. In addition, naltrexone was detected qualitatively. This method was used to analyse human plasma samples from a clinical trial after oral administration of a heroin/naloxone formulation in healthy volunteers. O-methylcodeine was used as an internal standard. Samples were kept in an ice-bath during their processing to minimize the degradation of heroin. A short methodology based on protein precipitation with methanol was used for sample preparation. After protein precipitation, only the addition of a formic acid solution was needed to elute heroin, 6-monoacetylmorphine, morphine, naloxone and naltrexone. Morphine metabolites were evaporated to dryness and reconstituted in a formic acid solution. Chromatographic separation was achieved at 35 °C on an X-Bridge Phenyl column (150 × 4.6 mm, 5 μm) using a gradient elution with a mobile phase of ammonium formate buffer at pH 3.0 and formic acid in acetonitrile. The run time was 8 min. The analytes were monitored using a triple quadrupole mass spectrometer with positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode. The method was found to be linear in a concentration range of 10-2000 ng/mL for M3G and 10-1000 ng/mL for the rest of compounds. Quality controls showed accurate values between -3.6% and 4.0% and intra- and inter-day precisions were below 11.5% for all analytes. The overall recoveries were approximately 100% for all analytes including the internal standard. A rapid, specific, precise and simple method was developed for the determination of heroin, its metabolites, naloxone and naltrexone in human plasma. This method was successfully applied to a clinical trial in 12 healthy volunteers.

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An automated, highly sensitive LC-MS/MS assay for the quantification of the opiate antagonist naltrexone and its major metabolite 6β-naltrexol in dog and human plasma

Cited by 20 publications

References 17 publications

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

The pharmacokinetics of methadone and its metabolites in neonates, infants, and children

Development and validation of a sensitive assay for the quantification of imatinib using LC/LC‐MS/MS in human whole blood and cell culture

Development and validation of a bioanalytical method for the simultaneous determination of heroin, its main metabolites, naloxone and naltrexone by LC–MS/MS in human plasma samples: Application to a clinical trial of oral administration of a heroin/naloxone formulation

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