Simultaneous determination of dextromethorphan, dextrorphan and doxylamine in human plasma by HPLC coupled to electrospray ionization tandem mass spectrometry: Application to a pharmacokinetic study

BackgroundDoxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available.ObjectiveThe objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions.Study DesignThis was a single-center, randomized, single-dose, laboratory-blinded, two-period, two-sequence, crossover study.SettingThe study was conducted in a phase I clinical unit.Subjects and MethodsA single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography.ResultsIn total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug concentration [Cmax] 118.21 ng/mL, coefficient of variation [CV] 19.2%; mean area under the plasma concentration time curve from time zero to time t [AUCt] 1746.97 ng · h/mL, CV 31.6%) and in the fed state (mean Cmax 120.99 ng/mL, CV 15.0%; mean AUCt 1712.20 ng · h/mL, CV 26.7%). No statistically significant between-treatment differences were observed for any of the pharmacokinetic parameters under study. The fed: fasting ratios of the geometric least squares means with corresponding 90% confidence intervals for Cmax and AUCt were within the range of 80–125%.ConclusionHigh-fat, high-calorie food intake does not affect the kinetics of doxylamine in healthy subjects. The drug was safe and well tolerated by the subjects in this study.

show abstract

Section: Discussionmentioning

confidence: 99%

Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Recovery (RE) was assessed at three different concentrations by comparing the peak area of set 3 (pre-extraction spiked samples) with set 2 (post-extraction fortification samples). Matrix effect values in the range between 85 and 115% could be considered as negligible (Donato et al, 2012).…”

Section: Matrix Effect and Recoverymentioning

confidence: 99%

Pharmacokinetics and oral bioavailability of epimedin C after oral administration of epimedin C and Herba Epimedii extract in rats

Lee¹,

Hsueh³

et al. 2013

Biomedical Chromatography

View full text Add to dashboard Cite

Epimedin C, an ingredient of Herba Epimedii, has potential for treatment of cardiovascular disease and bone loss. However, there is still no sensitive analytical method to monitor epimedin C in biological samples. The goal of this study was to develop a sensitive and reliable method based on a LC-MS/MS for evaluating the pharmacokinetics of epimedin C after administration of Herba Epimedii in rat. Electrospray ionization in positive-ion mode and multiple reaction monitoring were used to identify and quantitate active components. Analytes were separated by a reverse-phase C18 column. Liquid-liquid extraction using ethyl acetate, evaporation and reconstitution was used to plasma sample preparation. Mass transition of precursor ion → product ion pairs were monitored at m/z 823.4 → 313.1 for epimedin C and m/z 237.1 → 178.9 for carbamazepine (internal standard). A calibration curve gave good linearity (r > 0.999) over the concentration range 2.5-500 ng/mL. Pharmacokinetic data demonstrated that there was rapid distribution and slow elimination after epimedin C administration (1 mg/kg, i.v.). Oral bioavailabilities of epimedin C in the pure compound and in the Herba Epimedii were around 0.58% and 0.13%, respectively. The result suggests that other herbal ingredients of Herba Epimedii may suppress the oral bioavailability of epimedin C.

show abstract

“…[10,11] These slight differences could be explained by the analytical method that was used. [11,12] On the other hand, the fact that no significant sequence effect was observed in either the fasting or the fed treatment period of the study indicates that the washout period was appropriate and that no carryover effect was present. The effect of sex was studied as AUC = area under the plasma concentration-time curve; AUC t = AUC from time zero to time t; AUC ¥ = AUC from time zero extrapolated to infinity; C max = maximum plasma drug concentration; CV = coefficient of variation; k e = elimination rate constant; ln = log-normal; t ½ = elimination half-life; t max = time to reach C max .…”

Section: Discussionmentioning

confidence: 92%

Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets

et al. 2012

View full text Add to dashboard Cite

Background: Doxylamine succinate, an ethanolamine-based antihistamine, is used in the short-term management of insomnia because of its sedative effects. The data available on the pharmacokinetic profile of doxylamine in humans are limited, notwithstanding that this drug has been marketed in European countries for more than 50 years. In fact, no data on the effect of food on the pharmacokinetic parameters of doxylamine are available. Objective: The objective of this study was to evaluate the pharmacokinetic parameters of doxylamine following a single oral dose of doxylamine hydrogen succinate 25 mg in healthy human subjects under fed and fasting conditions. Study Design: This was a single-center, randomized, single-dose, laboratoryblinded, two-period, two-sequence, crossover study. Setting: The study was conducted in a phase I clinical unit. Subjects and Methods: A single oral dose of doxylamine hydrogen succinate 25 mg (equivalent to 17.4 mg of doxylamine base) was administered to healthy volunteers under either fed conditions (high-fat, high-calorie food intake) or fasting conditions in each study period. The drug administrations were separated by a wash-out period of seven calendar days. Plasma samples were collected for up to 60 hours postdose, and plasma doxylamine concentrations were determined by a high-performance liquid chromatography method with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. Results: In total, 24 healthy subjects (12 male and 12 female) were included in the study. Doxylamine succinate 25 mg tablets exhibited similar oral bioavailability of doxylamine in the fasting state (mean maximum plasma drug

show abstract

Simultaneous determination of dextromethorphan, dextrorphan and doxylamine in human plasma by HPLC coupled to electrospray ionization tandem mass spectrometry: Application to a pharmacokinetic study

Cited by 19 publications

References 22 publications

Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets

Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets

Pharmacokinetics and oral bioavailability of epimedin C after oral administration of epimedin C and Herba Epimedii extract in rats

Food Effects on the Pharmacokinetics of Doxylamine Hydrogen Succinate 25 mg Film-Coated Tablets

Contact Info

Product

Resources

About