Regional distributions of curcumin and tetrahydrocurcumin in the liver and small intestine of rats when orally co-administered with quercetin and paeoniflorin.

Curcumin (CUR), derived from the dietary spice turmeric, is a polyphenolic compound with various biological and pharmacological activities. Tetrahydrocurcumin (THC) is one of the major reductive metabolites of curcumin. A pharmacokinetic study using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) for the simultaneous determination of curcumin, THC, quercetin (QR), and paeoniflorin (PF) in rat plasma had been performed. In this study, the regional distributions of curcumin and tetrahydrocurcumin in the liver and the three segments of small intestine (duodenum, jejunum, and ileum) of rats when orally co-administered with quercetin and paeoniflorin were carried out. Drug concentrations were determined using UHPLC-MS/MS. The results showed that curcumin was well distributed in the small intestine, while the distributions of tetrahydrocurcumin in the liver, duodenum, jejunum were similar, but much more abundant in the ileum. When orally co-administered with quercetin and paeoniflorin, the tissue to plasma concentration ratios (Kp values) of curcumin in the three segments of the small intestine were increased, indicating that the presence of quercetin and paeoniflorin increases the distribution of curcumin in these regions. Moreover, the half-life (t1/2 ) of THC in the liver was significantly prolonged, and the Kp value of THC in the liver was increased and the Kp values in the small intestine were decreased, suggesting that the combination of quercetin and paeoniflorin might suppress the metabolism of curcumin in the small intestine. In brief, the combination had an effect on the distributions of curcumin and tetrahydrocurcumin in the liver and small intestine of rats.

Population pharmacokinetics and limited sampling strategies of polymyxin B in critically ill patients.

OBJECTIVES: To characterize the pharmacokinetics (PK) of polymyxin B in Chinese critically ill patients. The factors significantly affecting PK parameters are identified, and a limited sampling strategy for therapeutic drug monitoring of polymyxin B is explored. METHODS: Thirty patients (212 samples) were included in a population PK analysis. A limited sampling strategy was developed using Bayesian estimation, multiple linear regression and modified integral equations. Non-linear mixed-effects models were developed using Phoenix NLME software. RESULTS: A two-compartment population PK model was used to describe polymyxin B PK. Population estimates of the volumes of central compartment distribution (V) and peripheral compartment distribution (V2), central compartment clearance (CL) and intercompartmental clearance (Q) were 7.857 L, 12.668 L, 1.672 L/h and 7.009 L/h. Continuous renal replacement therapy (CRRT) significantly affected CL, and body weight significantly affected CL and Q. The AUC0-12h of polymyxin B in patients with CRRT was significantly lower than in patients without CRRT. CL and Q increased with increasing body weight. A limited sampling strategy was suggested using a two-sample scheme with plasma at 0.5h and 8h after the end of infusion (C0.5 and C8) for therapeutic drug monitoring in the clinic. CONCLUSIONS: A dosing regimen should be based on body weight and the application of CRRT. A two-sample strategy for therapeutic drug monitoring could facilitate individualized treatment with polymyxin B in critically ill patients.

Development and validation of UHPLC-MS/MS method for simultaneous quantification of escitalopram and its major metabolites in human plasma and its application in depressed patients.

Escitalopram, one of the Selective Serotonin Reuptake Inhibitors (SSRIs), has been widely used in the patients with major depression. In this study, a simple, sensitive and rapid method was established and validated for simultaneous quantification of Escitalopram (S-CT), desmethyl escitalopram (S-DCT), didemethyl escitalopram (S-DDCT) and escitalopram N-Oxide (S-NOCT) in human plasma by ultra-high performance liquid chromatography-tandem with mass spectrometry (UHPLC-MS/MS). Analytes were extracted from plasma by utilizing protein precipitation and then separated on a Hypersil GOLD C18 column (50 mm × 2.1 mm, 1.9 µm). The mobile phase was water: acetonitrile (70:30, v/v) with 0.25% formic acid at a flow-rate of 0.3 mL/min, within a 5 min run time. The mass analysis used positive electro-spray ionization (ESI) in selection reaction monitoring (SRM). The calibration ranges of the analytes were: S-CT: 2.0-200.0 ng/mL, S-DCT: 1.0-100.0 ng/mL, S-DDCT: 0.5-50.0 ng/mL, S-NOCT: 0.2-20.0 ng/mL. The method has been fully validated for selectivity, linearity, accuracy, precision, matrix effect, recovery, stability and carry over and all the results met the admissible limits according to the the US Food and Drug Administration guidelines. Mean plasma concentration (ng/mL) of S-CT, S-DCT, S-DDCT and S-NOCT in 93 depressed patients were 51.10 ± 45.73, 10.32 ± 15.25, 1.53 ± 1.79 and 0.87 ± 0.94, respectively. it is the first time that a UHPLC-MS/MS method for simultaneous quantification of S-CT and its 3 metabolites in human plasma was established and validated.

Determination of IQZ23 in rat plasma using LC-MS/MS: consideration for matrix effect and internal standard interference.

Aim: IQZ23, a novel ß-indoloquinazoline derivative, is a potential therapeutic agent for obesity and related metabolic disorders. To assist pharmacokinetics evaluation, a quantitative method for IQZ23 in rat plasma is required. Methods & Results: An LC-MS/MS assay for the determination of IQZ23 in rat plasma was developed and validated for the first time. Chromatographic conditions were optimized to ameliorate matrix effect with direct monitoring of typical phospholipids, including phosphatidylcholine and lysophosphatidylcholine. The structural analog internal standard (SYSU-3d) was set at a proper concentration to avoid analyte sensitivity loss caused by internal standard interference. The well-validated method was employed in the pharmacokinetics study of IQZ23 in Sprague-Dawley rats. Conclusion: This study provided valuable references for the further preclinical study of IQZ23.

Bioequivalence study of two formulations of memantine hydrochloride tablets in healthy male Chinese subjects under fasting and fed conditions.

PURPOSE: Memantine is currently the only drug that acts on the glutamate energy system to treat Alzheimer's disease. A generic memantine tablet was developed to offer an alternative to the marketed tablet formulation. The purpose of this study was to assess the bioequivalence of two different memantine formulations among healthy male Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS: We carried out single-center, randomized, single-dose, open-label, two-period, cross-over studies which including 20 healthy male Chinese subjects under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 240 hours after dosing. Key pharmacokinetic parameters including area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t), area from time zero to infinite (AUC0-∞), and Cmax were used for bioequivalence assessment. RESULTS: Under fasting condition, the 90% CIs of the geometric mean ratios of the test/reference drug for memantine were 106.5 - 114.0% for Cmax, 99.4 - 107.9% for AUC0-t, and 100.0 - 109.6% for AUC0-∞. Under fed condition, the 90% CIs of the geometric mean ratios of the test/reference drug for memantine were 94.8 - 104.3% for Cmax, 98.2 - 110.5% for AUC0-t, and 99.2 - 113.0% for AUC0-∞. CONCLUSION: The observed pharmacokinetic parameters of memantine of the test drug were similar to those of the reference formulation both in the fasting and fed state. That is to say, the test formulation of memantine 10-mg tablet is bioequivalent to the reference formulation (Ebixa 10-mg tablet).

Simultaneous determination of canrenone, digoxin and tolvaptan by UHPLC-MS/MS: application in heart failure patients.

Aim: Heart failure patients are frequently given comedication of digoxin and diuretics like spironolactone and tolvaptan. A UHPLC-MS/MS assay for determining canrenone (main active metabolite of spironolactone), digoxin and tolvaptan simultaneously should be developed so as to support related drug-drug interaction studies. Results: A UHPLC-MS/MS method for simultaneous determination of these three drugs in human plasma was established and fully verified as per CFDA guidelines. Chromatographic separation was achieved using a 4-min isocratic elution. Mass analyses were performed under positive electrospray ionization mode. The calibration curves were established over 1.0-400.0 ng/ml for canrenone and tolvaptan while over 0.1-40.0 ng/ml for digoxin. Conclusion: The developed method was feasible in detecting concentration and related drug-drug interaction studies.

Prognosis and related risk factors of patients with scarred uterus complicated with central placenta previa.

OBJECTIVES: To analyze the prognosis and related risk factors of patients with scarred uterus complicated with central placenta previa. MATERIAL AND METHODS: A total of 272 parturient women admitted to our hospital between June 2013 and December 2016 were selected, of whom 142 cases with central placenta previa were designated as a control group and another 130 with scarred uterus complicated with central placenta previa were allocated as an observation group. The delivery outcomes of the two groups were compared, and the influencing factors were comprehensively analyzed. RESULTS: The prenatal and postpartum blood losses of the observation group were significantly higher than those of the control group (P < 0.05). The incidence rates of placental adhesion, placenta accreta, hysterectomy and puerperal infection in the obstetric group significantly exceeded those of the control group (P < 0.05). Logistic regression analysis showed that postpartum hemorrhage and placenta implantation were risk factors affecting prognosis (P < 0.05). CONCLUSIONS: Patients with scarred uterus and central placenta previa suffered from serious complications such as profuse postpartum hemorrhage and placental adhesion after delivery. Particular attention should be paid to women with scarred uterus during subsequent pregnancy to prevent placenta previa and to reduce the risks of delivery, thereby benefiting prognosis evaluation.

Simultaneous determination of curcumin, tetrahydrocurcumin, quercetin, and paeoniflorin by UHPLC-MS/MS in rat plasma and its application to a pharmacokinetic study.

Curcumin (CUR) is a bioactive compound present in many composite prescriptions of traditional Chinese medicine together with quercetin (QR) and paeoniflorin (PF). Little is known about the influence of QR and PF on the absorption and metabolism of CUR when the three compounds are orally co-administered. In this study, a rapid, sensitive, and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous determination of CUR, tetrahydrocurcumin (THC), QR, and PF in rat plasma by using tinidazole as the internal standard (IS). A liquid-liquid extraction method with ethyl acetate was used to pre-treat the plasma samples. Chromatographic separation was conducted on a C18 column with isocratic elution using acetonitrile and 0.1% formic acid water solution (80:20, v/v) as the mobile phase at the flow rate of 0.3 mL/min. A TSQ Quantum Access Max API mass spectrometer equipped with electrospray ionisation (ESI) source in selection reaction monitoring (SRM) mode was employed to determine transitions of m/z 369.0 → 176.9, 373.1 → 137.0, 303.0 → 228.9, 478.9 → 120.9, 248.1 → 121.0 for CUR, THC, QR, PF, and IS, respectively. The selectivity, precision, accuracy, extraction recovery, matrix effect, and stability of the method were validated. This developed and validated method was successfully applied in the pharmacokinetic study of CUR, THC, QR, and PF in rats. The effects of QR and PF on the pharmacokinetics of CUR and its metabolite, THC, were evaluated in the plasma of Sprague-Dawley rats that were orally co-administered CUR, QR, and PF. The results showed that the combined use of QR, PF, and CUR has a possible influence on the metabolism and excretion of CUR. Our work provides a fundamental method for the rapid simultaneous determination of CUR, THC, QR, and PF in rat plasma. Furthermore, this study will provide a basic method for the analysis of pharmacokinetic interaction of CUR, QR, and PF and offer a scientific basis for a possible combination therapy with the three compounds.