A Pharmacokinetic Study of Ephedrine and Pseudoephedrine after Oral Administration of Ojeok-San by Validated LC-MS/MS Method in Human Plasma.

A sensitive and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) system was developed and fully validated for the simultaneous determination of ephedrine and pseudoephedrine in human plasma after oral administration of the herbal prescription Ojeok-san (OJS); 2-phenylethylamine was used as the internal standard (IS). Both compounds presented a linear calibration curve (r2 ≥ 0.99) over a concentration range of 0.2-50 ng/mL. The developed method was fully validated in terms of selectivity, lower limit of quantitation, precision, accuracy, recovery, matrix effect, and stability, according to the regulatory guidelines from the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety. This validated method was successfully applied for the pharmacokinetic assessment of ephedrine and pseudoephedrine in 20 healthy Korean volunteers administered OJS.

Pharmacokinetics of guaifenesin, pseudoephedrine and hydrocodone in a combination oral liquid formulation, administered as single and multiple doses in healthy Chinese volunteers, and comparison with data for individual compounds formulated as Antuss®.

1. A new oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone is effective in improving the symptoms of common cold. The pharmacokinetic properties of the individual components were evaluated in a randomized, open-label, four-period study in 12 healthy Chinese volunteers following single and multiple doses. The data were compared with data for the individual ingredients in Antuss®. 2. In the single-dose period, exposure levels (AUC and Cmax) for guaifenesin, pseudoephedrine and hydrocodone increased directly as the dose of the oral liquid formulation increased from 5 to 15 mL. Only minor amounts of guaifenesin and hydrocodone were excreted in urine (∼0.10% and 4.66%, respectively). Pseudoephedrine was mainly excreted unchanged, with 44.95% of the dose excreted in urine within 24 h. After multiple dosing, there was no obvious accumulation of any drug, as assessed by AUC. When considering Cmax, there was a trend toward accumulation of hydrocodone and pseudoephedrine. The pharmacokinetic profiles of guaifenesin and pseudoephedrine in the oral liquid formulation were similar to those in the branded preparation, Antuss®. 3. The newly developed oral liquid formulation combining guaifenesin, pseudoephedrine and hydrocodone was safe and well tolerated and might provide a reliable alternative to the branded formulation for patients with common colds.

Correlation between the transdermal characteristics of pseudoephedrine and amygdalin in majiepingchuan in vitro.

OBJECTIVE: To analyze the transdermal profile of pseudoephedrine and amygdalin in the Traditional Chinese Medicine majiepingchuan in rat skin and to reveal their interaction. METHODS: A Franz diffusion cell was used in vitro to evaluate the transdermal parameters of cumulative transdermal flux (Q(tot)), cumulative transmission (T(tot)), and mean penetration rate (Kp) of pseudoephedrine and amygdalin in majiepingchuan. Linear regression analyses of Q(tot) over time of pseudoephedrine vs amygdalin and their ratios was adopted for correlation evaluation. RESULTS: At 1, 2, 4, 6, and 8 h, the Q(tot), T(tot) and Kp of pseudoephedrine showed a good correlation with that of amygdalin. CONCLUSION: There was a small difference in the ratios of Q(tot), T(tot) and Kp between pseudoephedrine and amygdalin, and a correlation between them.

Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch.

1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson's disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration. 2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1 mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5 mg (2 and 4 cm(2)) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t1/2), time to peak plasma-concentration (Tmax), mean residence time (MRT), area under the curve (AUC(0-t)) were significantly (p < 0.05) different between transdermal and oral administrations. 3. The plasma half-life (t1/2) of rasagiline (1.25 mg patch: 11.8 ± 6.5 h, 2.5 mg patch: 12.5 ± 4.7 h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1 mg tablet: 4.7 ± 2.5 h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5 mg patches compared with 1 mg rasagiline tablet. The prolonged t1/2 and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet.

Simultaneous determination of levocetirizine and pseudoephedrine in dog plasma by liquid chromatography-mass spectrometry in the presence of dextrocetirizine.

PURPOSE: This study describes the development of a rapid and sensitive LC-ESI-MS assay for simultaneous enantioselective determination of levocetirizine and pseudoephedrine in dog plasma in the presence of dextrocetirizine. METHODS: Separations were achieved on an Ultron ES-OVM chiral column using the mobile phase consisting of 10 mM aqueous NH4OAc (pH 6.6) and acetonitrile (9:1 v/v). RESULTS: The retention times of pseudoephedrine, dextrocetirizine, levocetirizine and diazepam (internal standard) were 5.2, 8.3, 9.6 and 11.6 min, respectively, and the total run time was less than 15 min. The assay was validated to demonstrate the linearity, accuracy and precision, recovery and stability. The calibration curves were linear over the concentration range from 1 - 200 ng/mL for levocetirizine and from 5 - 1000 ng/mL for pseudoephedrine. CONCLUSIONS: The developed assay was successfully applied to a pharmacokinetic study after oral administration of the racemic cetirizine (0.5 mg/kg, or 0.25 mg/kg as levocetirizine) and pseudoephedrine (12 mg/kg) in the dog. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Application of a rapid and selective method for the simultaneous determination of carebastine and pseudoephedrine in human plasma by liquid chromatography-electrospray mass spectrometry for bioequivalence study in Korean subjects.

We describe a simple, rapid and sensitive high-performance liquid chromatography-electrospray ionization tandem mass spectrometric method that was developed for the simultaneous determination of carebastine and pseudoephedrine in human plasma using cisapride as an internal standard. Acquisition was performed in multiple-reaction monitoring mode by monitoring the transitions: m/z 500.43 > 167.09 for carebastine and m/z 166.04 > 147.88 for pseudoephedrine. The devised method involves a simple single-step liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a C(18) reversed-phase chromatographic column at 0.2 mL/min by isocratic elution with 10 mM ammonium formate buffer-acetonitrile (30:70, v/v; adjusted to pH 3.3 with formic acid). The devised method was validated over 0.5-100 ng/mL of carebastine and 5-1000 ng/mL of pseudoephedrine with acceptable accuracy and precision, and was successfully applied to a bioequivalence study involving a single oral dose (10 mg of ebastine plus 120 mg of pseudoephedrine complex) to healthy Korean volunteers.

Simultaneous determination of methylephedrine and pseudoephedrine in human urine by CE with electrochemiluminescence detection and its application to pharmacokeinetics.

A novel method for the determination of ephedra alkaloids (methylephedrine and pseudoephedrine) was developed by electrophoresis capillary (CE) separation and electrochemiluminesence detection (ECL). The use of ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate, BMIMBF(4)) improved the detection sensitivity markedly. The conditions for CE separation, ECL detection and effect of ionic liquid were investigated in detail. The two ephedra alkaloids with very similar structures were well separated and detected under the optimum conditions. The limits of detection (signal-to-noise ratio = 3) in standard solution were 1.8 x 10(-8) mol/L for methylephedrine (ME) and 9.2 x 10(-9) mol/L for pseudoephedrine (PSE). The limits of quantitation (signal-to-noise ratio = 10) in human urine samples were 2.6 x 10(-7) mol/L for ME and 3.6 x 10(-7 )mol/L for PSE. The recoveries of two alkaloids at three different concentration levels in human urine samples were between 81.7 and 105.0%. The proposed method was successfully applied to the determination of ME and PSE in human urine and the monitoring of pharmacokinetics for PSE. The proposed method has potential in therapeutic drug monitoring and clinical analysis.

Interaction of pseudoephedrine and azithromycin with losartan: Spectroscopic, dissolution and permeation studies.

This study aims at investigating the potential effect of selected cationic drugs (azithromycin (AZN) and pseudoephedrine sulfate (PSD) on the dissolution profile and intestinal permeation of losartan potassium (LOS) that might occur due to ion pair salt formation. DSC, FT-IR and 1H NMR indicated the formation of ion pair salts between LOS and each of AZN and PSD. Based on NMR chemical shifts calculations, utilizing specialized software, the most likely structures of the salt were proposed and revealed interesting structural features. The obtained ion pair products were shown to have lower aqueous solubilities (water and phosphate buffer pH 6.8) and higher apparent partition coefficient values compared to the parent compound. Neither of the cations affected the dissolution of LOS tablet (Cozaar® 100 mg) in the studied media (HCl pH 1.2 and phosphate buffer pH 6.8). Interestingly, AZN significantly increased the dissolution of LOS in phosphate buffer pH 4.5 (f2 = 33), and an explanation based on distinguished association pattern between AZN and LOS (CH/π) was offered. Employing permeation test across Caco-2 cells monolayer, the apparent permeability coefficient (Papp) of LOS increased significantly (from 0.9 × 10-5 cm/s to 1.8 × 10-5 cm/s) in the presence of the selected cations. Therefore, while the employed cationic drugs were not shown to form ion pair salts under the in-vitro dissolution conditions, they may still participate in significant in-vivo interaction with LOS.

Pharmacokinetic of pseudoephedrine in rat serum with luminol-pepsin chemiluminescence system by flow injection analysis.

Pepsin (Pep) accelerated the electron transferring rate of excited 3-aminophathlate and enhanced luminol-dissolved oxygen chemiluminescence (CL) intensity, and the flow injection (FI) luminol-Pep CL system was first developed. It was found that the CL intensity of luminol-Pep reaction could be remarkably inhibited by pseudoephedrine (PE); the decrement of CL intensity was linear to the logarithm of PE concentration in the range of 0.1∼100.0 nmol L(-1) with a detection limit of 0.03 nmol mL(-1) (3σ). At a flow rate of 2.0 mL min(-1), the complete process including washing and sampling was performed within 40 s, offering a sample throughput of 90 h(-1). This proposed method was successfully applied to determining PE in rat serum for 18 h after intragastric administration with the elimination ratio of 42.34 % and recoveries from 90.3 to 110.6 %. The pharmacokinetic results showed that PE could be rapidly absorbed into serum with peak concentration (C max) of 1.45 ± 0.18 g L(-1) at the time (T max) of 1.49 ± 0.02 h; the absorption half-life (0.35 ± 0.04 h), elimination half-life (1.86 ± 0.24 h), the area under curve (109.81 ± 6.03 mg L(-1) h(-1)), mean residence time (3.82 ± 0.27 h), and elimination rate constant (2.26 ± 0.23 L g(-1) h(-1)) in rats vivo were derived, respectively. The possible CL mechanism of luminol-Pep-PE reaction was discussed by FI-CL, fluorescence, and molecular docking (MD) methods.

Simultaneous quantification and pharmacokinetics of alkaloids in Herba Ephedrae-Radix Aconiti Lateralis extracts.

The combination of Herba Ephedrae (Mahuang in Chinese) and Radix Aconiti Lateralis (Fuzi in Chinese) is a classical preparation in traditional Chinese medicine and used for treating colds and rheumatic arthralgia. However, herbal medicines containing ephedrines and Aconitum alkaloids are strictly regulated because of the potential for adverse effects on the cardiovascular system and the central nervous system. We aimed to investigate the pharmacokinetics of 11 alkaloids in the Mahuang-Fuzi combination and single-herb extracts after oral administration in rats. The alkaloids were norephedrine, norpseudoephedrine, ephedrine, pseudoephedrine, methylephedrine, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine and benzoylhypaconine. Simultaneous determination of the alkaloids, including two pairs of diastereomers, was achieved in 14.5 min by a simple, rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method. The separation was performed on a Zorbax SB-Aq column (100 mm × 2.1 mm, 3.5 µm) at a flow rate of 0.3 mL/min using acetonitrile-0.1% formic acid aqueous solution as the mobile phase. The validated method demonstrated adequate sensitivity, selectivity and process efficiency for the quantitative analysis of complex herbal components. Compared with single-herb extracts, alkaloids in plasma (except methylephedrine, benzoylmesaconine and benzoylhypaconine) showed slower elimination (the mean residence time or half-life was longer), although the maximum plasma concentration and area under the plasma concentration curve values decreased. Accumulation may occur with continuous drug intake. These results suggest that drug monitoring may be essential for the safe use of the Mahuang-Fuzi combination.

Pseudoephedrine and preexercise feeding: influence on performance.

PURPOSE: This study examined the influence of preexercise food intake on plasma pseudoephedrine (PSE) concentrations and subsequent high-intensity exercise. In addition, urinary PSE concentrations were measured under the same conditions and compared with the present threshold of the World Anti-Doping Agency (WADA). METHODS: Ten highly trained male cyclists and triathletes (age = 30.6 ± 6.6 yr, body mass [BM] = 72.9 ± 5.1 kg, and V˙O2max = 64.8 ± 4.5 mL·kg·min; mean ± SD) undertook four cycling time trials (TT), each requiring the completion of a set amount of work (7 kJ·kg BM) in the shortest possible time. Participants were randomized into a fed or nonfed condition and orally ingested 2.8 mg·kg BM of PSE or a placebo (PLA) 90 min before exercise; in the fed trials, they consumed a meal providing 1.5 g·kg BM of CHO. Venous blood was sampled at 30, 50, and 70 min and pre-warm-up and postexercise for the analysis of plasma PSE and catecholamine concentrations, and urine was also collected for the analysis of PSE concentration. RESULTS: Independent of the preexercise meal, 2.8 mg·kg BM of PSE did not significantly improve cycling TT performance. The fed trials resulted in lower plasma PSE concentrations at all time points compared with the nonfed trials. Both plasma epinephrine and blood lactate concentrations were higher in the PSE compared with the PLA trials, and preexercise and postexercise urinary PSE concentrations were significantly higher than the threshold (150 µg·mL) used by WADA to determine illicit PSE use. CONCLUSION: Irrespective of the preexercise meal, cycling TT performance of approximately 30 min was not improved after PSE supplementation. Furthermore, 2.8 mg·kg BM of PSE taken 90 min before exercise, with or without food, resulted in urinary PSE concentrations exceeding the present WADA threshold.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of acrivastine and pseudoephedrine in human plasma and its application in pharmacokinetics.

A specific, sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of acrivastine and pseudoephedrine in human plasma samples. Plasma samples were processed and analyzed on a Phenomenex Luna 3 µ CN 100A column (150 mm×2.0 mm) eluted with the mobile phase consisting of methanol and 0.01 mol/L ammonium acetate water solution containing 0.1% formic acid (45:55, v/v) at a flow rate of 0.2 mL/min. The analytes were detected by positive ion electrospray ionization in multiple reaction monitoring mode. The transitions of m/z 349→278, m/z 166→148 and m/z 256→167 were monitored for acrivastine, pseudoephedrine and diphenhydramine (IS), respectively. The method was specific and sensitive with a lower limit of quantitation (LLOQ) of 1.52 ng/mL for acrivastine and 8.13 ng/mL for pseudoephedrine. The method showed good linearity in the range of 1.52~606.0 0 ng/mL for acrivastine and 8.13~813.12 ng/mL for pseudoephedrine (r≥0.996). The mean recovery were ranged 91.82% ~ 98.46% for acrivastine and 90.77% ~ 92.05% for pseudoephedrine. Validation results, such as accuracy, precision and repeatability were within the required limits. The method was successfully applied in a pharmacokinetic study of the acrivastine and pseudoephedrine hydrochloride compound capsule in humans.

Reverse-phase liquid chromatography with electrospray ionization/mass spectrometry for the quantification of pseudoephedrine in human plasma and application to a bioequivalence study.

A sensitive and selective reverse-phase liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method was developed and validated to quantify pseudoephedrine (CAS 90-82-4) in human plasma. Phenacetin was used as the internal standard (I.S.). Sample preparation was performed with a deproteinization step using acetonitrile. Pseudoephedrine and I.S. were successfully separated using gradient elution with 0.5% trifluoroacetic acid (TFA) in water and 0.5% TFA in methanol at a flow-rate of 0.2 mL/min. Detection was performed on a single quadrupole mass spectrometer by a selected ion monitoring (SIM) mode via electrospray ionization (ESI) source. The ESI source was set at positive ionization mode. The ion signals of m/z 166.3 and 180.2 were measured for the protonated molecular ions of pseudoephedrine and I.S., respectively. The lower limit of quantification (LLOQ) of pseudoephedrine in human plasma was 10 ng/mL and good linearity was observed in the range of concentrations 10-500 ng/mL (R2 = 1). The intra-day accuracy of the drug containing plasma samples was more than 97.60% with a precision of 3.99-11.82%. The inter-day accuracy was 99.36% or more, with a precision of 7.65-18.42%. By using this analytical method, the bioequivalence study of the pseudoephedrine preparation was performed and evaluated by statistical analysis of the log transformed mean ratios of pharmacokinetic parameters. All the results fulfilled the standard criteria of bioequivalence, being within the 80-125% range which is required by the Korea FDA, US FDA, and EMEA to conclude bioequivalence. Consequently, the developed reverse-phase LC-ESI-MS method was successfully applied to bioequivalence studies of pseudoephedrine in healthy male volunteers.

Pharmacokinetics of pseudoephedrine in rats, dogs, monkeys and its pharmacokinetic-pharmacodynamic relationship in a feline model of nasal congestion.

The objectives of these studies were to characterize the pharmacokinetics (PK) of the nasal decongestant pseudoephedrine (PSE) in rats, dogs, and monkeys, and to evaluate its lower gastrointestinal tract regional bioavailability in rats. An LC-MS/MS assay with a lower limit of quantification (LLOQ) of 0.4 ng/mL of plasma was developed for the analysis of PSE in animal plasma. The total body clearance (CL) was the highest in rats (78 mL/min/kg), lowest in monkeys (15 mL/min/kg) and the dog averaged in between (33 mL/min/kg). The volume of distribution at steady state (Vdss) ranged from 3-5 L/kg in all species. In rats and dogs, the mean half-lives (t1/2) was ≈1.5 hr, while in monkeys the mean t1/2 was 4.6 hr, comparable to that observed in adult humans (4-8 hr). The oral bioavailability was 38, 58 and 78% in rats, dogs and monkeys. The bioavailability following intra-ileum or intra-colonic administration in rats was superior to that following oral dosing (66% and 78%, respectively) suggesting that colonic absorption may be compensating for the short half-life, thus enabling successful QD sustained release formulations of PSE. The pharmacokinetic/pharmacodynamic relationship (PK/PD) of PSE was also investigated in a feline model of nasal congestion to establish efficacious trough concentrations in cats for a comparison with that in humans. The PK/PD in the cat model followed a sigmoid Emax model with an EC50 (plasma concentration that elicits 50% of the maximum response) of 0.32 ±0.05 (SD) µM consistent with human plasma concentrations required for efficacy.

Analysis of stimulants in oral fluid and urine by gas chromatography-mass spectrometry II: pseudophedrine.

This study was designed to optimize a method for the identification and quantification of ephedrines in oral fluid (OF) and for its application to subjects taking different doses of pseudoephedrine. Ephedrines use by athletes is banned by World Anti-Doping Agency (WADA), only "in competition" if their concentration in urine exceeds the cutoff limit. The study aimed to establish if there is a correlation in terms of times of elimination and of concentration trends of ephedrine in OF and urine after administration of therapeutic doses of pseudoephedrine to various subjects. Results obtained from excretion studies performed on eight subjects showed reproducible times of disappearance of ephedrines from OF. Pseudoephedrine was generally at low concentrations or undetectable in oral fluid samples 12 h after administration, whereas urine samples collected in the same period of time showed higher ephedrine concentrations and exceeding cutoff values generally between 8 and 24 h after administration of the drug. Within- and between-individual variability was observed in terms of concentrations of pseudoephedrine in OF following the administration of the same dose. Only in the case of sustained-release drugs were constant pseudoephedrine concentrations achieved in OF.

Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.

Influences of urinary pH on the pharmacokinetics of three amphetamine-type stimulants using a new high-performance liquid chromatographic method.

A simple and sensitive high-performance liquid chromatographic (HPLC) method after precolumn derivatization with 9,10-anthraquinone-2-sulfonyl chloride (ASC) has been developed and validated for the analysis of amphetamine-type stimulants (ATS) in biological samples. Based on this method, we investigated the impact of urinary pH on the pharmacokinetics of phenylpropanolamine (PPA), pseudoephedrine (PSE), and fenfluramine (FEN) in rats. The drugs were orally administrated to rats, which had been induced, by repeated oral doses of ammonium chloride or sodium bicarbonate, to excrete urine at lower or higher pH than the normal value, respectively. Results revealed that as the increase of urinary pH, the mean elimination half-life (t(1/2)), the mean residence time (MRT) and the area under the plasma concentration-time curve (AUC) of PPA, PSE, and FEN were greatly raised, while the total plasma clearance (CL/F) decreased considerably. These findings have important clinical implications.