Influence of Phenobarbital on Morphine Metabolism and Disposition:LC-MS/MS Determination of Morphine (M) and Morphine-3-Glucuronide (M3G) in Wistar-Kyoto Rat Serum, Bile, and Urine

Alnouti, Yazen; Shelby, Melinda K.; Chen, Chuan; Klaassen, Curtis D.

doi:10.2174/138920007779315026

Cited by 7 publications

(15 citation statements)

References 50 publications

(59 reference statements)

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“…In more recent studies, serum M3G AUC values were also reported to be approximately twofold higher in female compared with male Wistar rats. 25 Morphine-3-glucuronide has been shown previously to act supraspinally to attenuate morphine antinociception. 26 Hence, higher circulating M3G concentrations in female compared with male rats following acute morphine administration would be expected to result in greater attenuation of morphine antinociception in female compared with male rats in the hot plate test, consistent with the experimental observations reported herein.…”

Section: Discussionmentioning

confidence: 99%

Antinociception Versus Serum Concentration Relationships Following Acute Administration of Intravenous Morphine in Male and Female Sprague‐dawley Rats: Differences Between the Tail Flick and Hot Plate Nociceptive Tests

South

Edwards

Smith

2009

Clin Exp Pharma Physio

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1. Antinociception versus serum morphine concentration relationships were defined in male and female Sprague-Dawley rats administered single intravenous (i.v.) bolus doses of morphine, using the hot plate (2.1-14 mg/kg) and tail flick tests (1-8 mg/kg). 2. Serum concentrations of morphine and morphine-3-glucuronide (M3G), its major metabolite in the rat, were assayed using high-performance liquid chromatography (HPLC) with electrochemical detection. 3. Significantly higher (P < 0.05) values of peak antinociception (approximately 1.7-fold), as well as the extent and duration of antinociception (approximately fourfold), were observed in male compared with female rats administered 10 mg/kg morphine in the hot plate test. Although there were no significant sex-related differences in the area under the serum morphine concentration versus time curve (AUC) at this dose, systemic exposure to M3G (M3G AUC) was significantly higher (approximately twofold; P < 0.05) in female than male rats. 4. In contrast with most previous studies investigating sex differences in morphine antinociception in rats, the antinociceptive effects of single i.v. doses of morphine (1-8 mg/kg) in the tail flick test did not differ significantly between male and female rats. 5. Morphine ED(50) and EC(50) values (95% confidence intervals) for antinociception in the hot plate test were significantly lower (P < 0.05) in male rats (ED(50) 8.4 mg/kg (7.6-9.2); EC(50) 1.8 nmol/L (1.5-2.1)) compared with female rats (ED(50) 10.6 mg/kg (9.1-12.0); EC(50) 3.7 nmol/L (3.4-4.1)). However, in the tail flick test, there was no significant difference between male and female rats in ED(50) (1.8 (0.4-3.3) and 1.4 mg/kg (0.4-2.5), respectively) or EC(50) (0.5 (0.3-0.6) and 0.4 nmol/L (0.2-0.5), respectively) values. 6. Supraspinal attenuation of morphine antinociception by M3G may account for these differences.

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Section: Discussionmentioning

confidence: 99%

Antinociception Versus Serum Concentration Relationships Following Acute Administration of Intravenous Morphine in Male and Female Sprague‐dawley Rats: Differences Between the Tail Flick and Hot Plate Nociceptive Tests

South

Edwards

Smith

2009

Clin Exp Pharma Physio

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“…The glucuronides of morphine are one of the most important reactive phase II metabolites, with their importance lying in the fact that morphine-3-O-glucuronide is an inactive metabolite, whereas morphine-6-O-glucuronide possesses pharmacological activity greater than that of the parent compound. Therefore, numerous quantitative LC/MS methods have been developed for the simultaneous detection of morphine, M3G, and M6G in human urine [149][150][151] plasma [141][142]150,152], and meconium [21], rat plasma and hair [153], bile and urine [154], whole blood and brain tissue [155], and dog and monkey plasma [156]. M3G is a typical opiate monitored in the confirmatory analysis for multiple drugs of abuse in plasma and urine [73,157].…”

Section: Quantitative Lc/ms Analysismentioning

confidence: 99%

Direct Analysis of Glucuronides with Liquid Chromatography-Mass Spectrometric Techniques and Methods

Ketola¹,

Hakala

2010

CDM

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Glucuronidation is one of the main phase II metabolic reactions in humans and animals. A variety of analytical techniques and methods have been used for the detection and quantification of glucuronides of both endogenous and xenobiotic compounds from different biological samples of humans and animals. Drug metabolism has been extensively studied with both in vitro and in vivo experiments under various conditions. The purpose of this review is to explore in detail the benefits and drawbacks of different liquid chromatography-mass spectrometric (LC/MS) methods and techniques in detection and identification of all forms of glucuronide conjugates from in vitro, biological, and environmental samples. The entire analytical procedure is covered, from sample treatment, separation, and ionization to qualitative and quantitative analyses. The aim of this review is not to cover every published paper where glucuronides are identified and/or quantified, but rather to focus on special cases where a new analytical approach or technical development has led to a better, more specific, or more comprehensive detection, identification, or quantitation of glucuronide conjugates.

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“…Morphine is the most commonly-used opiate analgesic for the treatment of severe pain [1,2]. In humans, the major metabolites of morphine are morphine-3b-glucuronide (M3G) and morphine-6b-glucuronide (M6G) [3 -5].…”

Section: Introductionmentioning

confidence: 99%

“…Both of these metabolites are pharmacologically active, but have opposite effects. The effects of M6G have been reported to be equal to or greater than morphine [6 -8], while M3G counteracts morphine's analgesic activity [1,6]. Published reports have shown that these glucuronide metabolites may be formed in different amounts in other animals that may be used in pharmacokinetic or pharmacodynamic drug studies [9 -15].…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous analysis of morphine‐related compounds in plasma using mixed‐mode solid phase extraction and UltraPerformance liquid chromatography–mass spectrometry

Fountain¹,

Yin

Diehl

2009

J of Separation Science

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A bioanalytical method using mixed-mode solid phase extraction and UltraPerformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the analysis of morphine, morphine-3beta-glucuronide, morphine-6beta-glucuronide, 6-acetylmorphine, morphine N-oxide, and 10-hydroxymorphine in porcine plasma. All six compounds, along with four deuterated internal standards, were simultaneously extracted using mixed-mode strong cation exchange SPE in a 96-well microElution plate format. Due to analyte instability, a neutralizing solvent was used during the elution step to minimize degradation of 6-acetylmorphine. Separation was subsequently performed in 8 minutes on a 2.1 x 100 mm, 1.8 microm C(18 )column designed for retention of extremely polar compounds using a formic acid and methanol gradient. Analytes were detected by positive electrospray ionization in multiple reaction monitoring mode using a fast-scanning triple quadrupole mass spectrometer. Recovery was 73-123% depending on the analyte, and inter-day variability was less than 6%. Linearity was determined in porcine plasma by spiking the analytes prior to SPE. Correlation coefficients were >or= 0.998, and% deviation from the actual concentrations was less than 15%. The lower limit of quantitation (LLOQ) for all compounds was between 0.1 and 0.25 ng/mL.

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Influence of Phenobarbital on Morphine Metabolism and Disposition:LC-MS/MS Determination of Morphine (M) and Morphine-3-Glucuronide (M3G) in Wistar-Kyoto Rat Serum, Bile, and Urine

Cited by 7 publications

References 50 publications

Antinociception Versus Serum Concentration Relationships Following Acute Administration of Intravenous Morphine in Male and Female Sprague‐dawley Rats: Differences Between the Tail Flick and Hot Plate Nociceptive Tests

Antinociception Versus Serum Concentration Relationships Following Acute Administration of Intravenous Morphine in Male and Female Sprague‐dawley Rats: Differences Between the Tail Flick and Hot Plate Nociceptive Tests

Direct Analysis of Glucuronides with Liquid Chromatography-Mass Spectrometric Techniques and Methods

Simultaneous analysis of morphine‐related compounds in plasma using mixed‐mode solid phase extraction and UltraPerformance liquid chromatography–mass spectrometry

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