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1.
Biomed Chromatogr ; 35(4): e5031, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33217008

ABSTRACT

This study aimed to develop a highly selective, sensitive and fast liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the determination of obacunone in rat plasma. Sample preparation was accomplished by a simple solid-phase extraction procedure. Chromatographic separation was carried out on an ACQUITY BEH C18 column using acetonitrile/methanol (1:1, v/v) and 0.1% formic acid in water as mobile phase at a flow rate of 0.4 mL/min. Quantification was performed with multiple reactions monitoring in positive ion mode with the precursor-to-product ion transitions at m/z 455.2 > 161.1 for obacunone and m/z 515.2 > 161.1 for nomilin (internal standard). The assay was demonstrated to be linear over the concentration range of 0.1-1,000 ng/mL with correlation coefficient >0.999 (r > 0.999). The intra- and inter-day accuracy ranged from -8.33 to 10.40%, while the precision was <10.41%. The mean extraction recovery was >75.32%, and the assay was free of matrix effect. The validated LC-MS/MS method was successfully applied to the pharmacokinetic study of obacunone in rats after oral and intravenous administrations. The oral bioavailability of obacunone was 13.59%.


Subject(s)
Benzoxepins , Chromatography, Liquid/methods , Limonins , Solid Phase Extraction/methods , Tandem Mass Spectrometry/methods , Animals , Benzoxepins/blood , Benzoxepins/isolation & purification , Benzoxepins/pharmacokinetics , Limonins/blood , Limonins/isolation & purification , Limonins/pharmacokinetics , Linear Models , Male , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and Specificity
2.
Clin Toxicol (Phila) ; 55(2): 142-146, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27967233

ABSTRACT

CONTEXT: Oxetorone is a serotonin antagonist antimigraine drug but literature relating to its toxic properties is poor. The aim of this study is to describe the toxicological profile of oxetorone and to highlight any relationship between clinical and analytical findings. MATERIALS AND METHODS: This is a retrospective and observational study of cases exposure to oxetorone, reported to the Angers Poison and Toxicovigilance Centre between January 2002 and May 2016. Severity was assessed using the Poisoning Severity Score (PSS). Cases where data were incomplete, where oxetorone was deemed not accountable, where clinical signs were linked mainly to a co-ingested drug or where the plasma concentration of oxetorone was negative were all excluded. RESULTS: We included 43 cases of exposure, 31 of whom were suicide attempts. The assumed ingested dose (60-3600 mg) was correlated to severity (rs = 0.45, p = 0.01). Symptoms of moderate severity (PSS2 = drowsiness, hypertonia, myosis, convulsions, arterial hypotension, QRS widening, QTc prolongation) were observed following ingestion of more than 600 mg of oxetorone (median dose =1200 mg) and severe symptoms (PSS 3 = coma, convulsions, QTc prolongation, QRS widening, ventricular tachycardia, arterial hypotension, cardiogenic shock) were observed starting from 1800 mg (median dose =2700 mg). In four cases, a secondary worsening of symptoms 10-48 h following ingestion was observed. Plasma oxetorone was measured in four patients. Severe symptoms were observed in the event of a concentration over 0.3 mg/L and the highest measured serum oxetorone level was delayed by 20-48 h following the ingestion for two cases. CONCLUSIONS: Several clinical and paraclinical parameters strongly point towards membrane-stabilising properties of the molecule and the risk of a delayed occurrence of symptoms or a secondary worsening.


Subject(s)
Benzoxepins/poisoning , Poison Control Centers , Serotonin Antagonists/poisoning , Suicide, Attempted/statistics & numerical data , Adolescent , Adult , Aged , Benzoxepins/blood , Child , Child, Preschool , Drug Overdose , Female , Humans , Infant , Male , Middle Aged , Retrospective Studies , Serotonin Antagonists/blood , Time Factors , Young Adult
3.
Planta Med ; 82(3): 224-9, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26544116

ABSTRACT

Nomilin is a potential anticancer agent. In this study, a rapid, sensitive, and simple ultra-performance liquid chromatography with tandem mass spectrometry methodology was established and validated to quantify nomilin in rat plasma. Plasma samples were prepared through liquid-liquid extraction using ethyl acetate. Chromatographic separation was performed using an Acquity HSS T3 column. Acetonitrile and water containing 0.1% (v/v) formic acid were used as mobile phases at a flow rate of 0.3 mL/min. Nomilin and quercetin (internal standard) were detected and quantified via a triple quadrupole tandem mass spectrometer in the positive ion mode with multiple reaction monitoring. Tandem mass spectrometry detection was performed by monitoring the fragmentations of m/z 515.3 → m/z 161.0 and m/z 303.2 → m/z 153.1 of nomilin and quercetin, respectively. Good linearity (R(2) > 0.996) was observed in the concentration range of 1 ng/mL to 500 ng/mL with a lower limit of quantification of 1 ng/mL for nomilin. The average extraction recoveries of nomilin and quercetin were > 82.3% and 82.0%, respectively. Intra- and interday precisions were less than 15% and accuracy ranged from 85.0% to 90.1%. Indeed, the proposed method was successfully applied to analyze the pharmacokinetics of nomilin after 3 and 50 mg/kg nomilin were administered to rats via intravenous and oral routes, respectively.


Subject(s)
Benzoxepins/blood , Chromatography, High Pressure Liquid/methods , Limonins/blood , Tandem Mass Spectrometry/methods , Animals , Benzoxepins/pharmacokinetics , Limonins/pharmacokinetics , Liquid-Liquid Extraction , Male , Rats , Rats, Sprague-Dawley
4.
Drug Metab Lett ; 10(1): 22-37, 2016.
Article in English | MEDLINE | ID: mdl-26031460

ABSTRACT

UNLABELLED: MLN3897 is a small molecule antagonist of the C-C chemokine receptor-1. Since preclinical studies showed that the molecule was metabolized into two halves, the metabolism, excretion, and pharmacokinetics of MLN3897 were investigated in humans using MLN3897 14C-radiolabeled either on the chlorophenyl (CP) or the tricyclic (TC) half of MLN3897 after an oral dose. OBJECTIVE: To evaluate the mass balance, metabolism and pharmacokinetics of MLN3897 in two cohorts of six randomized healthy subjects. METHOD: After receiving informed consent, subjects were dosed after an overnight fast of 10-hours followed by at least 4- hours after dosing on day-1. Each cohort received a single 29 mg oral dose of either the CP or the TC as an oral solution in water. Serial blood samples, urine and feces were collected over a 10-day period post-dose. RESULTS: For both radiolabeled moieties, 55-59% of the dose was recovered in feces and 32% recovered in urine. MLN3897 was metabolized extensively in humans, with minor amounts of intact MLN3897 detected in the urine and feces. N-oxidation of the tricyclic moiety (M28) and N-dealkylation of the piperidinyl moiety were the primary metabolic pathways leading to further formation of the carboxylic acid metabolite (M19) and the (4-(4-chlorophenyl)-3,3- dimethylpiperidin-4-ol) metabolite (M40). Oxidative metabolites M11, M19, M28, M44 were present at >10% of the total circulating radioactivity and also at >25% of MLN3897 exposure. Metabolites resulting from the chlorophenyl-labeled moiety (M40) had significantly more systemic exposure compared to the tricyclic-labeled moiety (M19).


Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Receptors, CCR1/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/blood , Anti-Inflammatory Agents/urine , Benzoxepins/administration & dosage , Benzoxepins/blood , Benzoxepins/pharmacokinetics , Benzoxepins/urine , Biotransformation , Carboxylic Acids/metabolism , Dealkylation , Feces/chemistry , Female , Humans , Intestinal Elimination , Magnetic Resonance Spectroscopy , Male , Oxidation-Reduction , Pyridines/administration & dosage , Pyridines/blood , Pyridines/pharmacokinetics , Pyridines/urine , Rats, Sprague-Dawley , Receptors, CCR1/metabolism , Renal Elimination
5.
Article in English | MEDLINE | ID: mdl-23611843

ABSTRACT

A rapid and selective ultra high performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of four major ingredients in Cortex Dictamni extract, including limonin, dictamnine, obacunone and fraxinellone in rats plasma. Nimodipine was used as the internal standard. Following extraction by methyl tert-butyl ether, the analytes were separated on a Thermo Syncronis C18 column by a gradient elution within a runtime of 9min. The mobile phase consisted of A (methanol) and B (2mmol/L ammonium acetate in water). The detection was accomplished by using positive ion electrospray ionization in multiple reaction monitoring mode. The method was linear for all analytes over investigated range with all correlation coefficients greater than 0.998. The lower limits of quantification were 9.18ng/mL for limonin, 12.0ng/mL for dictamnine, 16.05ng/mL for obacunone and 4.59ng/mL for fraxinellone. The intra- and inter-day precision (RSD%) was within 10% and the accuracy (RE%) ranged from -12.9% to 9.7%. This rapid and sensitive method was fully validated and successfully applied to the pharmacokinetic study of limonin, dictamnine, obacunone and fraxinellone in the rat plasma after oral administration of Cortex Dictamni extract.


Subject(s)
Benzofurans/blood , Benzoxepins/blood , Chromatography, High Pressure Liquid/methods , Drugs, Chinese Herbal/pharmacokinetics , Limonins/blood , Quinolines/blood , Administration, Oral , Animals , Benzofurans/administration & dosage , Benzoxepins/administration & dosage , Drugs, Chinese Herbal/administration & dosage , Limonins/administration & dosage , Male , Quinolines/administration & dosage , Rats , Rats, Sprague-Dawley , Rutaceae/chemistry , Sensitivity and Specificity , Tandem Mass Spectrometry/methods
6.
Mol Carcinog ; 52(1): 49-56, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22086836

ABSTRACT

In this study, we evaluated chemopreventive efficacy of Antitumor B, a Chinese herbal mixture of six plants (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus arvensis L., Dictamnus dasycarpus, and Dioscorea bulbifera) on the development of 4-nitroquinoline-1-oxide (4NQO) induced oral squamous cell carcinomas in A/J mice. Antitumor B, delivered through diet, inhibited 4NQO-induced oral cancer development by 59.19%. The reduction of cell proliferation appears to be associated with efficacy of Antitumor B against 4NQO-induced oral cancer in A/J mice. The expression of epidermal growth factor receptor (EGFR) and phosphorylated EGFR (Tyr1173) were down-regulated by Antitumor B. Tissue distribution of Antitumor B was determined using obacunone, matrine, and maackiain as marker chemicals. We found significant amounts of obacunone, matrine, and maackiain in the blood after 1-wk treatment. The concentrations of these three compounds did not increase further at 18 wk, suggesting that plasma concentrations had reached a steady-state level at 1 wk. There was no significant body weight loss and there was no other obvious sign of toxicity in Antitumor B-treated mice. These results suggest that Antitumor B is a promising agent for human oral cancer chemoprevention.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Squamous Cell/prevention & control , Drugs, Chinese Herbal/therapeutic use , Mouth Neoplasms/prevention & control , 4-Nitroquinoline-1-oxide/toxicity , Alkaloids/blood , Animals , Benzoxepins/blood , Biomarkers/blood , Carcinogens/toxicity , Carcinoma, Squamous Cell/chemically induced , Carcinoma, Squamous Cell/drug therapy , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/chemically induced , Cell Transformation, Neoplastic/drug effects , Chemoprevention , ErbB Receptors/biosynthesis , Limonins/blood , Male , Mice , Mouth Neoplasms/chemically induced , Mouth Neoplasms/drug therapy , Phosphorylation , Pterocarpans/blood , Quinolizines/blood , Tyrosine/metabolism , Matrines
7.
J Chromatogr B Biomed Appl ; 687(2): 419-25, 1996 Dec 13.
Article in English | MEDLINE | ID: mdl-9017466

ABSTRACT

A simple and sensitive method for quantitation of HSR-609 (I) in human plasma and urine was developed using HPLC with the fluorescence labelling reagent 4-(N,N-dimethylaminosulfonyl)-7-N-piperazino-2,1,3-benzox adi azole (DBD-PZ). Compound I was extracted from human plasma and urine, and derivatized by reaction with DBD-PZ in the presence of Mukaiyama reagent A, an equimolar solution of 2,2'-dipyridyl disulfide (DPDS) and triphenylphosphine (TPP) in acetonitrile. The reaction mixture was cleaned up by liquid liquid extraction following the derivatization. The conjugate was analyzed by ion-pair-HPLC with fluorometric detection. The quantitation limits for I were 0.5 ng/ml in plasma and 5 ng/ml in urine. Using this method, plasma concentration and urinary excretion of I were studied after oral administration of I to human volunteers.


Subject(s)
Benzoxepins/analysis , Chromatography, High Pressure Liquid/methods , Histamine H1 Antagonists/analysis , Pyridines/analysis , Benzoxepins/blood , Benzoxepins/pharmacokinetics , Benzoxepins/urine , Fluorescence , Histamine H1 Antagonists/blood , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/urine , Humans , Male , Oxadiazoles , Piperazines , Pyridines/blood , Pyridines/pharmacokinetics , Pyridines/urine , Reproducibility of Results , Sensitivity and Specificity , Sulfonamides
8.
J Toxicol Clin Toxicol ; 28(1): 111-6, 1990.
Article in English | MEDLINE | ID: mdl-2381017

ABSTRACT

The authors report a case of severe self-poisoning with oxetorone. Plasma concentration of the drug assessed by HPLC was a thousand times higher than therapeutic levels. Coma, convulsions, and cardiac conduction defects were observed, similar to those noted with tricyclic and tetracyclic antidepressant poisoning. Similar cardiac disorders consisting of conduction defects had not been previously described during oxetorone intoxication.


Subject(s)
Benzoxepins/poisoning , Coma/chemically induced , Seizures/chemically induced , Adult , Benzoxepins/blood , Chromatography, High Pressure Liquid , Clonazepam/therapeutic use , Electrocardiography , Emergencies , Female , Gastric Lavage , Heart Conduction System/drug effects , Humans , Seizures/drug therapy
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