The major metabolite of duloxetine is a glucuronide conjugate of 4-hydroxy duloxetine (4-HD). However, interestingly, there have been no reports determining concentrations of 4-HD and no fully validated method has been established for measuring duloxetine and 4-HD in rat plasma. We developed a method for the simultaneous quantification of duloxetine and its metabolite in rat plasma using high-performance liquid chromatography tandem mass spectrometry. Duloxetine and 4-HD were analyzed on a reverse-phase C 18 analytical column after protein precipitation of the plasma sample with methanol, using carbamazepine as an internal standard. The isocratic mobile phase of 5 mM ammonium acetate-methanol (4:6, v/v) was eluted at 0.4 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transition monitored in selective reaction monitoring mode. The coefficient of variation for assay precision was <18.0%, and the accuracy was 84.0-118.0%. This method was successfully used to measure the concentrations of duloxetine and its metabolite in plasma following the oral administration of a single 40 mg/kg dose in rats. Copyright © 2013 John Wiley & Sons, Ltd.Keywords: duloxetine; 4-hydroxy duloxetine (4-HD); rat plasma; LC/MS/MS Duloxetine hydrochloride, chemically known as (+)-N-methyl-3 (1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride, is a potent inhibitor of both serotonin and norepinephrine reuptake that binds to 5-hydroxytryptamine (5-HT) and norepinephrine (NE) transport sites with comparable affinities. It is used clinically for the treatment of major depressive disorders, pain owing to diabetic peripheral neuropathy and incontinence (Ma et al., 2007). The major metabolite of duloxetine is a glucuronide conjugate of 4-hydroxy duloxetine (Lantz et al., 2003). Estimations of duloxetine in biological matrices using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) have been reported (Zhao et al., 2009Radhe et al., 2012, and HPLC has been used to quantify 4-hydroxy duloxetine-b-D-glucuronide in human plasma (Satonin et al., 2007). However, there have been no reports determining concentrations of 4-hydroxy duloxetine (4-HD) and no fully validated method has been established for measuring duloxetine and 4-hydroxy duloxetine in rat plasma.Here, we present a simple, sensitive HPLC-MS/MS method for the simultaneous determination of duloxetine and its metabolite in rat plasma. This method was successfully used to characterize the pharmacokinetics of duloxetine and 4-HD following the oral administration of duloxetine in rats.Duloxetine and 4-HD were purchased from Waterstone Technology (Carmel, IN, USA) and Santa Cruz Biotechnology (Santa Cruz, CA, USA). Carbamazepine, used as an internal standard (IS), was purchased from Sigma Chemical (St Louis, MO, USA). HPLC-grade methanol was obtained from Merck (Darmstadt, Germany). Duloxetine and 4-HD were dissolved in methanol at 1 mg/mL. These standard solutions were diluted serially ...
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