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Stereoselective and simultaneous measurement of cis- and trans-isomers of doxepin and N-desmethyldoxepin in plasma or urine by high-performance liquid chromatography

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Abstract

Doxepin is a tricyclic antidepressant marketed as an irrational mixture of cis- and trans-geometric isomers in the ratio of 15:85. A convenient high-performance liquid chromatographic (HPLC) procedure for simultaneous quantitation of geometric isomers of doxepin and N-desmethyldoxepin in plasma and urine is described. The HPLC procedure employed a normal phase system with a silica column and a mobile phase consisting of hexane-methanol-nonylamine (95:5:0.3, v/v/v), a UV detector and nortriptyline as the internal standard. The liquid-liquid extraction solvent was a mixture of n-pentane-isopropanol (95:5, v/v). The limit of quantitation was 1 ng/ml for each isomer. The calibration curves were linear over the ranges 1–200 ng/ml (plasma) and 1–400 ng/ml (urine). In plasma, the accuracy (mean±S.D.) (97.53±1.67%) and precision (3.89±1.65%) data for trans-doxepin were similar to corresponding values for urine, i.e., 97.10±2.40 and 3.82±1.14%. Accuracy and precision data for trans-N-desmethyldoxepin in plasma were 97.57±2.06 and 4.38±3.24%, and in urine were 97.64±3.32 and 5.26±1.83%, respectively. Stability tests under three different conditions of storage indicated no evidence of degradation. The recovery of doxepin was 61–64% from plasma and 63–68% from urine. The method has been applied to analyses of plasma and urine samples from human volunteers and animals dosed with doxepin.

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    Other methods report simultaneous estimation of Dox and NDox in a variety of biological samples like whole blood [5], gastric fluids [5], bile, urine [5], cerebrospinal fluid [5], tissues [5], hair [7], urine [11] and human plasma [11–13]. A majority of these methods were developed for forensic or toxicological studies but only few of them addressed the pharmacokinetics of Dox and NDox in human plasma [11,13]. Moreover, they have limited sensitivity (lower limit of quantitation) in the range of 0.25–100 ng/mL for both the analytes.

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    Gas liquid chromatography, high performance liquid chromatography, thin-layer chromatography, and capillary electrophoresis [13–26] have been applied to determination of doxepin in biological fluids. Gas chromatography and high performance liquid chromatography have been also used for separation or quantify low concentrations of doxepin geometric isomers [27–29]. Some studies have proposed potentiometric sensors [30] to be used in determination of doxepin cation in a substance and in its pharmaceutical preparations.

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