A sensitive and selective liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of domperidone (CAS number: 57808-66-9) in human plasma using paracetamol (CAS number: 103-90-2) as an internal standard (IS). Domperidone and paracetamol in plasma were extracted with ethyl acetate, separated on a C18 reversed phase column, eluted with mobile phase of acetonitrile-glacial acetic acid (0.3%) (40:60, v/v), ionized by positive ion pneumatically assisted electrospray and detected in the multi-reaction monitoring mode using precursor→product ions of m/z 426.2→175.1 for domperidone and 152→110 for the IS, respectively. The calibration curve was linear (r2≥0.99, n=5) over the concentration range of 0.2-80 ng/mL and with lower limit of detection and quantitation of 0.05 and 0.2 ng/mL. The specificity, matrix effect, recovery, sensitivity, linearity, accuracy, precision, and stabilities were validated for domperidone in human plasma. In conclusion, the validation results showed that this method was sensitive, economical and less toxic and it can successfully fulfill the requirement of clinical pharmacokinetic study of domperidone oral preparation in Chinese healthy volunteers.
This single-dose study in healthy Chinese fasted volunteers was shown that the ibuprofen test and reference met the requirement of the State Food and Drug Administration, and the test and reference were bioequivalent.
The purpose of this study is to determine the concentrations of norcantharidin (CAS NO: 5442-12-6) in mouse tissues and investigate its tissue distribution after intragastric administration of disodium norcantharidate solution. A highly sensitive and specific liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated, using ribavirin (CAS NO: 36791-04-5) as the internal standard (IS). Norcantharidin and IS were extracted from 0.3 mL tissue homogenates using protein precipitation with acetone under acid condition. The analyte was separated on a C18 reverse phase column and analyzed by MS/MS in the multiple reaction monitoring (MRM) mode using ESI with positive ionization, m/z 169→123 for norcantharidin and m/z 267→135 for IS. The developed method was validated over a linear range of concentrations 0.01~5 μg·mL - 1 in liver, lung, kidney, stomach, small intestine, uterus and testis, 0.005~0.5 μg·mL - 1 in heart, spleen and brain, the correlation coefficients (r2) were between 0.9918 and 0.9976. The tissue distribution study result was as follows: The AUC0-t of norcantharidin in tissues was in the order as follows: small intestine, stomach, uterus, kidney, testis, liver, lung, spleen, heart, brain.
To investigate the pharmacokinetic characteristics of icariside II after a single oral dose administration of YiGu Capsule in healthy -Chinese volunteers. 8 (4 female) healthy Chinese volunteers were involved and administrated for 15 doses of YiGu Capsule after fasting overnight. 4 ml of blood samples were collected at scheduled time before and after administration. Icariside II in human plasma was separated on a Agela Venusil XBP-C18 column (250 mm×4.6 mm, 5 μm), and eluted using acetonitrile-water (containing 0.1% formic acid) (70:30, V/V) as mobile phase. The analytes were detected with a -triple quad HPLC-MS/MS using ESI with positive ionization. Ions monitored in the multiple reaction monitoring mode were m/z 515.1 (precursor ion) to m/z 369.1 (product ion) for icariside II and m/z 321.0 (precursor ion) to m/z 275.0 (product ion) for lorazepam (internal standard).The plasma concentration of icariside II was determined by established HPLC-MS/MS method after disposition and its pharmacokinetic parameters were analyzed and evaluated by PK Solver Software (version 1.0). The Cmax, Tmax, t1/2, AUC0-24, AUC0-∞, MRT0-∞-1, 2.50±1.91 h, 7.61±2.81 h, 12.68±4.86 ng · mL-1 · h, 14.22±5.75 ng · mL-1 · h, 9.55±1.56 h, 12.81±7.94 L · h-1 and 121.70±32.70 L. The established HPLC-MS/MS method was sensitive, selective and rapid for icariside II pharmacokinetic study.
The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.
A sensitive method for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites, isosorbide 2-mononitrate and isosorbide 5-mononitrate (IS-2-MN and IS-5-MN), in human plasma was developed using capillary gas chromatography with electron-capture detection, whereas 1,2,4-butanetriol trinitrate was used as internal standard. The analytes were extracted with a simple liquid-liquid extraction from plasma and separated on a DB-1 column. The results of method validation demonstrated that the calibration curves were linear in range of 2-60 ng/mL for ISDN and IS-5-MN, 1-20 ng/mL for IS-2-MN, respectively. The precision (RSD%) was less than 15%, and the lower limit of quantitation was identifiable and reproducible at 2 ng/mL for ISDN and IS-5-MN, 1 ng/mL for IS-2-MN. The analytes in plasma were stable after being stored for more than 30 days and after 2 freeze-thaw cycles (-20 to 25°C). And then this method was successfully applied to a pharmacokinetic investigation on isosorbide dinitrate oral spray in healthy volunteers.
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