Peculiarities of Pharmacokinetics and Bioavailability of Some Cardiovascular Drugs under Conditions of Antiorthostatic Hypokinesia.

We studied pharmacokinetics and bioavailability of verapamil, propranolol, and ethacizine in healthy volunteers after single oral administration under normal conditions and on the second day of simulated antiorthostatic hypokinesia modeling some effects of microgravity. Under conditions of antiorthostatic hypokinesia, a tendency to a decrease in half-elimination period, mean retention time, and volume of distribution and an increase in the rate of absorption, ratio of maximum concentrations, and relative rate of absorption of verapamil and propranolol were revealed. For ethacizine, a statistically significant increase in the time of attaining maximum concentration and volume of distribution and a decrease in the maximum concentration, rate of absorption, ratio of maximum concentrations, and relative rate of absorption under conditions of antiorthostatic hypokinesia were found.

A novel and sensitive UPLC-MS/MS method to determine mequitazine in rat plasma and urine: Validation and its application to pharmacokinetic studies.

The aim of this study was to develop an analytical method to determine mequitazine in rat plasma and urine. Mequitazine was separated by UPLC-MS/MS equipped with a Kinetex core-shell C18 column (50 × 2.1 mm, 1.7 µm) using 0.1% (v/v) aqueous formic acid and acetonitrile containing 0.1% (v/v) formic acid as a mobile phase by gradient elution at a flow rate of 0.3 mL/min. Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique operating in multiple reaction monitoring positive ion mode. Mass transitions were m/z 323.3 → 83.1 for mequitazine and 281.3 → 86.3 for imipramine as internal standard. Liquid-liquid extraction with ethyl acetate and protein precipitation with methanol were used for sample extraction. Chromatograms showed that the method had high resolution, sensitivity and selectivity without interference from plasma constituents. Calibration curves for mequitazine in rat plasma and urine were 0.02-200 ng/mL, showing excellent linearity with correlation coefficients (r2 ) >0.99. Both intra- and inter-day precisions (CV%) were within 4.08% for rat plasma and urine. The accuracies were 99.58-102.03%. The developed analytical method satisfied the criteria of international guidance. It could be successfully applied to pharmacokinetic studies of mequitazine after oral and intravenous administration to rats.

Evaluation of molecularly imprinted polymers for chlorpromazine and bromopromazine prepared by multi-step swelling and polymerization method-The application for the determination of chlorpromazine and its metabolites in rat plasma by column-switching LC.

Monodisperse molecularly imprinted polymers (MIPs) for chlorpromazine (CPZ) and bromopromazine (BPZ), MIPCPZ and MIPBPZ, were prepared using methacrylic acid as a functional monomer and ethylene glycol dimethacrylate as a crosslinker by multi-step swelling and polymerization. The retention and molecular-recognition properties of MIPCPZ and MIPBPZ were evaluated using a mixture of potassium phosphate buffer and acetonitrile or a mixture of water and acetonitrile including ammonium formate as a mobile phase in reversed-phase LC. On MIPBPZ, CPZ, BPZ and imipramine (IMP) gave the maximal retention factors at a mobile-phase pH 8, while the maximal imprinting factors were obtained at a mobile-phase pH 7. Each MIP recognized a template molecule the most, while CPZ metabolites, desmethyl CPZ (DM-CPZ), CPZ sulfoxide (CPZ-SO) and 7-hydroxy CPZ (7-OH-CPZ), were moderately recognized on MIPCPZ and MIPBPZ. Furthermore, both MIPs gave the similar retention and molecular-recognition for CPZ and its metabolites. For avoiding the template-leakage problems, MIPBPZ was used as the pretreatment column for the determination of CPZ and its metabolites in rat plasma in column-switching LC with UV detection. In addition to DM-CPZ and CPZ-SO, didesmethyl CPZ (DDM-CPZ) and CPZ N-oxide (CPZ-NO) were speculated as the metabolite in rat plasma after administration of CPZ using LC-ESI-TOF-MS, while 7-OH-CPZ was not detected. The column-switching LC method was validated and applied for the determination of CPZ and its metabolites, DM-CPZ, DDM-CPZ, CPZ-SO and CPZ-NO, in rat plasma after intravenous and oral administration of CPZ using IMP as an internal standard.

Assessment of Concentrations of Four Phenothiazine Antipsychotics in Serum and Whole Blood Using Different Diatomaceous Earth-based Solid-phase Columns: A Comparative Analysis.

This study attempted to determine the phenothiazine antipsychotics concentration in serum and whole blood samples using various diatomaceous earth-based solid-phase columns and elution solvents and subsequently evaluate their efficiency. Phenothiazine antipsychotics concentrations of 5 - 2000 ng/mL were extracted from serum and whole blood using each column. All compounds were analyzed using liquid chromatography-tandem mass spectrometry. Phenothiazine antipsychotics extraction in serum and whole blood using diatomaceous earth-based solid-phase columns seemed to have an affinity with the elution solvent.

Development and validation of a gas chromatography/tandem mass spectrometry method for simultaneous quantitation of several antipsychotics in human plasma and oral fluid.

RATIONALE: Antipsychotic drugs are prescription medications used to treat psychotic disorders, such as schizophrenia, schizoaffective disorder, or psychotic depression. With several antipsychotic drugs currently available all over the world, this class of drugs has quickly gained importance in both the clinical and forensic context. This work describes the development and validation of a methodology for the determination of seven antipsychotic drugs in plasma and oral fluid samples. METHODS: The antipsychotic drugs (chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, cyamemazine and, levomepromazine) were isolated from 0.2 mL of oral fluid and 0.5 mL of plasma using solid-phase extraction (SPE) following analysis by gas chromatography/tandem mass spectrometry (GC/MS/MS). The method was validated according to the international guidelines in terms of selectivity, linearity, accuracy, precision and recovery. RESULTS: The procedure was linear within 2-600 ng/mL (plasma) and 2-400 ng/mL (oral fluid), the intervals varying according to the compound; a mean R2 value of 0.99 was obtained and the calibrator's accuracy (mean relative error) was within a ±15 % interval for all concentrations. The limits of detection ranged from 1 to 10 ng/mL. Within- and between-run precision and accuracy were acceptable for all studied compounds. The extraction efficiency of the process ranged from 79% to 95%. The method was applied to authentic specimens. CONCLUSIONS: The described method was proven selective and sensitive for the determination of antipsychotics in low sample volumes using SPE and GC/MS/MS. This method was considered suitable not only for routine analysis of patients undergoing antipsychotic treatment (to evaluate compliance), but also in forensic scenarios where the studied compounds may be involved. To the best of our knowledge, this is the first work that reports the determination of antipsychotic drugs in oral fluid using MS/MS.

A sensitive LC-MS/MS method for analysis of pericyazine in presence of 7-hydroxypericyazine and pericyazine sulphoxide in human plasma and its application to a comparative bioequivalence study in Chinese healthy volunteers.

A robust and highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of pericyazine in human plasma. The plasma sample was alkalized with sodium hydroxide solution and handled by liquid-liquid extraction with ethyl acetate after adding perphenazine as an internal standard (IS). The analytes were separated on an Ultimate™ AQ-C18 analytical column at 40°C, with a gradient elution consisting of A (aqueous phase: 5mM ammonium acetate buffer solution containing 0.1% formic acid) and B (organic phase: acetonitrile) at a flow rate of 0.350mL/min. The detection was conducted on an API 4000 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) transitions, m/z 366.5>142.4 for pericyazine, m/z 382.5>142.4 for its 7-hydroxy and sulphoxide metabolites and m/z 404.3>171.3 for IS were chosen to achieve high selectivity in the simultaneous analyses. The method exhibited great improvement in sensitivity (LLOQ of 0.021ng/mL) and good linearity over the concentration range of 0.021-9.90ng/mL. The intra- and inter-day precision, accuracy, and stability results were within the acceptable limits and no matrix effect was observed. This method was successfully applied in a bioequivalence study to evaluate the pharmacokinetics in 20 healthy male Chinese volunteers. Additional exploratory analyses of 7-hydroxy and sulphoxide metabolites of pericyazine in the same samples suggest that the unchanged drug is predominant in the plasma and suitable for the bioequivalence comparison after a single oral administration of 10mg pericyazine.

Quantification of mequitazine in human plasma by gas chromatography- quadrupole mass spectrometry and its application to a human pharmacokinetic study.

A specific and sensitive gas chromatography-mass spectrometry (GC-MS) with quadrupole mass analyzer type was developed and validated for the quantitative analysis of mequitazine in human plasma. After liquid-liquid extraction of plasma samples containing mequitazine and promethazine (internal standard, IS) using hexane with pH adjustment, the extract was evaporated and an aliquot of reconstituted residue was injected into the GC-MS system. The assay showed linearity over a concentration range from 1 to 50 ng/mL. Intra- and inter-day precision for mequitazine was <9.09 and 9.29%, respectively, and intra- and inter-day accuracy ranged from -7.97 to 9.05% and from -1.51 to 7.89%, respectively. The lower limit of quantification was 1 ng/mL in the present assay. The developed analytical method was successfully applied to a pharmacokinetic study after a single oral administration of mequitazine in human subjects.

Electrochemical preparation of a molecularly imprinted polypyrrole modified pencil graphite electrode for the determination of phenothiazine in model and real biological samples.

A sensitive electrochemical sensor for determination of phenothiazine (PTZ) was introduced based on molecularly imprinted polymer (MIP) film. A computational study was performed to evaluate the template-monomer geometry and interaction energy in the prepolymerization mixture. The electrode was prepared during electropolymerization of pyrrole (Py) on a pencil graphite electrode (PGE) by cyclic voltammetry (CV) technique. The quantitative measurements were performed using differential pulse voltammetry (DPV) in Britton-Robinson (BR) buffer solutions using 60% (v/v) acetonitrile-water (ACN/H2O) binary solvent. The effect of important parameters like pH, monomer concentration, number of cycles, etc on the efficiency of MIP electrode was optimized and the calibration curve was plotted at optimal conditions. Two dynamic linear ranges of 1-300 µmol L(-1) and 0.5-10 mmol L(-1) were observed. The detection limit (based on S/N=3) of PTZ was obtained 3×10(-7) mol L(-1). The MIP/PGE has been successfully applied as a selective sensor for fast and accurate determination of PTZ in some model and real biological samples.

Photosafety screening of phenothiazine derivatives with combined use of photochemical and cassette-dosing pharmacokinetic data.

This study aimed to establish an efficient photosafety screening system, employing in vitro photochemical and cassette-dosing pharmacokinetic (PK) studies. Eight phenothiazine (PTZ) derivatives were selected as model chemicals, and photochemical characterization and cassette-dosing PK study were carried out. In vivo photosafety testing on oral PTZs (100 mg/kg) was also assessed in rats. All the tested PTZs exhibited potent UVA/B absorption with molar extinction coefficients of ca. 3400-4400 M(-1)cm(-1). Under exposure to simulated sunlight (2.0 mW/cm(2)), all PTZs, especially fluphenazine 2HCl (FP) and trifluoperazine 2HCl (TF), tended to generate reactive oxygen species (ROS). Casset-dosing PK studies demonstrated high dermal deposition of FP and TF in rats, and from these findings, taken together with the potent photochemical reactivity, both FP and TF were deduced to be highly phototoxic. In contrast, the phototoxic potential of chlorpromazine HCl (CP) seemed to be low because of moderate ROS generation and limited dermal distribution. Predicted phototoxic risk for PTZs from photochemical and PK data appeared basically to agree with the observed phototoxicity in rats; however, oral CP (100 mg/kg) caused severe phototoxic responses in rats. Metabolites of CP have been recognized to be phototoxic, which might explain in part this false prediction. These findings might also suggest the necessity of complementary testing on drug metabolites for more reliable photosafety evaluation. The combined use of photochemical and PK data might be efficacious for simple and fast prediction of the phototoxic potential of new drug candidates.

Spectrofluorimetric determination of certain biologically active phenothiazines in commercial dosage forms and human plasma.

A validated simple and sensitive spectrofluorimetric method was developed for the determination of chlorpromazine hydrochloride, promethazine hydrochloride, trifluperazine hydrochloride, thioridazine hydrochloride, perazine maleate and oxomemazine. The method was based on condensation of malonic acid/acetic anhydride (MAA) under the catalytic effect of the tertiary amine moiety of the studied phenothiazines to provide a deep yellow to brown colour with green fluorescence. Relative fluorescence intensity of the products was measured at λ exc 398 nm and λ em 432 nm. Different variables affecting the reaction were studied and optimized. The method was successfully applied for the determination of the studied drugs in commercial dosage forms. The lower detection limits allowed the application of this method for the determination of the compounds in plasma as an example of a biological fluid. In addition, the method was considered specific for the determination of tertiary amines in the presence of primary and secondary amines; as a result, it was deemed suitable for the determination of the cited drugs in the presence of their degradation products resulting from N-dealkylation or oxidation of the corresponding sulphoxides or sulphones.

Active cyamemazine metabolites in patients treated with cyamemazine (Tercian®): influence on cerebral dopamine D2 and serotonin 5-HT (2A) receptor occupancy as measured by positron emission tomography (PET).

RATIONALE: Cyamemazine (Tercian®) is an antipsychotic agent blocking central dopamine D(2) receptors, which induces few extrapyramidal adverse effects, due to a potent antagonistic action at serotonin 5-HT(2A) receptors. In vitro studies showed that the desmethyl metabolite of cyamemazine (N-desmethyl cyamemazine) has similar affinity for 5-HT(2A) receptors as cyamemazine, whereas its D(2) receptor affinity is eight times lower (Benyamina et al. in Eur J Pharmacol 578(2-3):142-147, 2008). Moreover, cyamemazine sulfoxide showed modest affinity for 5-HT(2A) receptors. OBJECTIVES: The objective of this study is to measure steady-state plasma levels of N-desmethyl cyamemazine and cyamemazine sulfoxide in patients treated with clinically relevant doses of cyamemazine and correlate them with dopamine D(2) and serotonin 5-HT(2A) receptor occupancies (RO) assessed by positron emission tomography (PET). METHODS: Eight patients received Tercian® 37.5, 75, 150, or 300 mg/day according to their symptoms. Dopamine D(2) and serotonin 5-HT(2A) RO were assessed at steady-state cyamemazine plasma levels using [(11)C]raclopride and [(11)C]N-methyl-spiperone, respectively, for PET. Plasma levels of cyamemazine metabolites were determined using a validated high-performance liquid chromatography (PerkinElmer) associated with a mass spectrometry detection (API 365, PE SCIEX). The apparent equilibrium inhibition constant (K (i)) was estimated by fitting RO with plasma levels of cyamemazine metabolites at the time of the PET scan. RESULTS: After 6 days of cyamemazine administration, plasma N-desmethyl cyamemazine reached steady-state levels at 2 to 12 times higher than those previously found for cyamemazine (Hode et al. in Psychopharmacology (Berl) 180:377-384, 2005). Plasma levels of N-desmethyl cyamemazine were closely related to striatal D(2) RO (r (2) = 0.942) and extrastriatal 5-HT(2A) RO (r (2) = 0.901). The estimated K (i(app)) value of N-desmethyl cyamemazine for striatal D(2) receptors was about fivefold higher than that for extrastriatal 5-HT(2A) receptors (48.7 vs. 10.6 nM). Striatal D(2) RO increased with the plasma levels of N-desmethyl cyamemazine but remained below 75% even at its highest levels. At steady state, plasma cyamemazine sulfoxide levels were about double those of N-desmethyl cyamemazine. However, these cyamemazine sulfoxide levels should not contribute significantly to in vivo 5-HT(2A) and D(2) receptor occupancy. CONCLUSIONS: In patients orally given cyamemazine, N-desmethyl cyamemazine, but not cyamemazine sulfoxide, should significantly contribute to in vivo frontal 5-HT(2A) and striatal D(2) receptor occupancy. The higher in vivo affinity of cyamemazine and its desmethyl metabolite for serotonin 5-HT(2A) receptors compared with dopamine D(2) receptors should explain the low incidence of extrapyramidal adverse effects.

Quantitative determination of phenothiazine derivatives in human plasma using monolithic silica solid-phase extraction tips and gas chromatography-mass spectrometry.

Solid-phase extraction (SPE) using micropipette tips is a useful technique to prepare samples prior to mass spectrometry. However, most commercial SPE tips have loading capacities that are insufficient for quantitative determination. In this paper, we describe a rapid method for quantitative microanalysis of five phenothiazine derivatives, chlorpromazine, levomepromazine, promazine, promethazine and trimeprazine, using a recently introduced C(18) monolithic silica SPE tip, the MonoTip C(18), for extraction from human plasma. The drugs could be extracted within 5 min from 0.1-mL plasma samples, eluted with methanol, and the eluate injected directly into a gas chromatograph prior to mass spectrometry analysis. Only 0.7 mL of solvent was required for each step of the extraction process. The recoveries of the five phenothiazines spiked into plasma were 91-95% and the limits of quantification for each drug were between 0.25 and 2.0 ng/0.1 mL. The maximum intra- and inter-day coefficient of variation was 11%. The validated method was successfully used to quantify the plasma concentration of levemepromazine in a human subject after oral administration of the drug. This new method is expected to have wide applications as a pretreatment for the rapid, quantitative determination of drug concentrations in plasma samples.

[Application of the clinoid dehydration method in forensic medical expert examination of poisoning with narcotic and strong medicine preparations].

The method of clinoid dehydration of biological fluids along with pH measurement is shown to be suitable for the diagnosis of narcotic intoxication and poisoning with narcotic and potent agents. The data obtained by this and conventional methods are compared. Diagnostically significant signs of narcotic intoxication are deduced from the hemogram of a dry blood droplet and serum pH values.

Fatal intoxication with milnacipran.

The antidepressant milnacipran is a double serotonin/noradrenalin reuptake inhibitor. The low reported incidence of intoxication indicates excellent tolerance in comparison with tricyclic and second generation antidepressants. We report a fatal intoxication associating milnacipran, at blood levels (femoral=21.5 mg/l, cardiac=20 mg/l) 40-fold higher than the usual treatment concentration, and six other molecules (fluoxetine, norfluoxetine, sertraline, cyamemazine, nordazepam and oxazepam) at therapeutic levels. To the best of our knowledge, this is the first reported fatal intoxication involving milnacipran.

Quantification of cationic anti-malaria agent methylene blue in different human biological matrices using cation exchange chromatography coupled to tandem mass spectrometry.

Selective and sensitive methods for the determination of the cationic dye and anti-malarial methylene blue in human liquid whole blood, dried whole blood (paper spot), and plasma depending on protein precipitation and cation exchange chromatography coupled to electrospray ionisation (ESI) tandem mass spectrometry (MS/MS) have been developed, validated according to FDA standards, and applied to samples of healthy individuals and malaria patients within clinical studies. Acidic protein precipitation with acetonitrile and trifluoroacetic acid was used for liquid whole blood and plasma. For the extraction of methylene blue from paper spots aqueous acetonitrile was used. Sample extracts were chromatographed on a mixed mode column (cation exchange/reversed phase, Uptisphere MM1) using an aqueous ammonium acetate/acetonitrile gradient. Methylene blue was quantified with MS/MS in the selected reaction monitoring mode using ESI and methylene violet 3RAX as internal standard. Depending on the sample volume (whole blood and plasma 250 microL, and 100 microL on paper spots) the method was linear at least within 75 and 10,000 ng/mL and the limit of quantification in all matrices was 75 ng/mL. Batch-to-batch accuracies of the whole blood, plasma, and paper spot methods varied between -4.5 and +6.6%, -3.7 and +7.5%, and -5.8 and +11.1%, respectively, with corresponding precision ranging from 3.8 to 11.8% CV. After a single oral dose (500 mg) methylene blue concentrations were detectable for 72 h in plasma. The methods were applied within clinical studies to samples from healthy individuals and malaria patients from Burkina Faso.

Simultaneous determination of some phenothiazine derivatives in human blood by headspace solid-phase microextraction and gas chromatography with nitrogen-phosphorus detection.

Chlorpromazine, levomepromazine, promazine, triflupromazine, and trimeprazine were simultaneously determined in human whole blood and plasma by combining headspace solid-phase microextraction and gas chromatography with nitrogen-phosphorus detection. Extraction efficiency for the phenothiazine derivatives was 0.013-0.117% for both sample types. Regression equations were linear [correlation coefficient (r) = 0.9951-0.9999] within the range 2.5-200 ng/0.5 mL for triflupromazine and trimeprazine, and 6.3-200 ng/0.5 mL for chlorpromazine, levomepromazine, and promazine. The limit of detection for each compound was 0.2-3.9 ng/0.5 mL whole blood and plasma. Intraday and interday coefficients of variation for all phenothiazines in both human samples were commonly < 15 and 20%, respectively. We also report the determination of levomepromazine in human plasma after oral administration.

[Extended suicidal poisoning with carbamazepine and phenothiazine derivatives]. / Rozszerzone samobójcze zatrucie karbamazepina i fenotiazynami.

UNLABELLED: Two cases (woman and man) of the extended suicidal poisonings with carbamazepine and phenothiazine derivatives are presented. Drug's blood concentrations during poisoning were monitored. We examine correlation between patient's general status and the drug's blood concentrations, carbamazepine and phenothiazine derivatives interaction due to young, healthy people who received no earlier treatment. MATERIAL AND METHODS: blood samples for toxicological examinations were collected at 0, 12, 24 and 48 hours after admission. Carbamazepine was determined using FPIA method and phenothiazines derivatives by HPLC-DAD. The highest blood concentrations were for carbamazepine: 30.92 mg/l (woman) and 20.95 ng/ml (man); for phenothiazine derivatives: 927 ng/ml (woman) and 733 ng/ ml (man). CONCLUSIONS: In both cases severe central nervous depression was observed due to summed action of the drugs. Sex and individual differences in cytochromes activities should have influence to carbamazepine metabolism and faster elimination time in woman. In the case of phenothiazine derivatives faster elimination time in man was observed. The differences in elimination times between compared drugs confirm their different metabolic routes.

Simple and simultaneous determination for 12 phenothiazines in human serum by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the simultaneous analysis of the 12 phenothiazines (chlorpromazine, fluphenazine, levomepromazine, perazine, perphenazine, prochlorperazine, profenamine, promethazine, propericiazine, thioproperazine, thioridazine and trifluoperazine) in human serum using HPLC/UV. The separation was achieved using a C(18) reversed-phase column (250 mm x 4.6 mm I.D., particle size 5 microm, Inersil ODS-SP). The mobile phase, consisting of acetonitrile-methanol-30 mM NaH(2)PO(4) (pH 5.6) (300:200:500, v/v/v), was delivered at a flow rate of 0.9 mL/min and UV detection was carried out at 250 nm. The recoveries of the 12 phenothiazines spiked into serum samples were 87.6-99.8%. Regression equations for the 12 phenothiazines showed excellent linearity, with detection limits of 3.2-5.5 ng/mL for serum. The inter-day and intra-day coefficients of variation for serum samples were commonly below 8.8%. The selectivity, accuracy and precision of this method are satisfactory for clinical and forensic purposes. This sensitive and selective method offers the opportunity for simultaneous screening and quantification of almost all phenothiazines available in Japan for the purposes of clinical and forensic applications.

Determination of mequitazine in human plasma by gas-chromatography/mass spectrometry with ion-trap detector and its pharmacokinetics after oral administration to volunteers.

The objective of this study was to develop an assay for mequitazine (MQZ) for the study of the bioavailability of the drug in human subjects. Using one mL of human plasma, the pH of the sample was adjusted and MQZ in the aqueous phase extracted with hexane; the organic layer was then evaporated to dryness, reconstituted and an aliquot introduced to a gas chromatograph/mass spectrometer (GC/MS) system with ion-trap detector. Inter- and intra-day precision of the assay were less than 15.1 and 17.7%, respectively; Inter- and intra-day accuracy were less than 8.91 and 18.6 %, respectively. The limit of quantification for the current assay was set at 1 ng/mL. To determine whether the current assay is applicable in a pharmacokinetic study for MQZ in human, oral formulation containing 10 mg MQZ was administered to healthy male subjects and blood samples collected. The current assay was able to quantify MQZ levels in most of the samples. The maximum concentration (Cmax) was 8.5 ng/mL, which was obtained at 10.1 h, with mean half-life of approximately 45.5 h. Under the current sampling protocol, the ratio of AUCt-->last to AUCt-->infinity was 93.4%, indicating that the blood collection time of 216 h is reasonable for MQZ. Therefore, these observations indicate that an assay for MQZ in human plasma is developed by using GC/MS with ion-trap detector and validated for the study of pharmacokinetics of single oral dose of 10 mg MQZ, and that the current study design for the bioavailability study is adequate for the drug.