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Liu R.,China Pharmaceutical University | Liu R.,Nanjing Clinical Technology Laboratories Inc. | Zheng L.,National Key Institute of Traditional Chinese Medicine Quality Control | Cheng M.,China Pharmaceutical University | And 9 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2016

Corynoline and acetycorynoline, the major active components derived from Corydalis bungeana Herba, showed multiple pharmacological activities. However, quantification of the two compounds in human urine has not been reported. A simple liquid chromatography with tandem mass spectrometry method for the simultaneous determination of corynoline and acetycorynoline in human urine has been developed and fully validated. The analytes were extracted from urine samples by simple liquid-liquid extraction. Chromatographic separation was achieved on a Hedera ODS-2C18 column with the mobile phase of water (containing 0.5% formic acid) and acetonitrile (28:72, v/v) at a flow rate of 0.4 mL/min. A tandem mass spectrometric detection was conducted using multiple reaction monitoring via an electrospray ionization source in positive mode. The monitored ion transitions were m/z 368.1 → 289.1 for corynoline, m/z 410.2 → 289.2 for acetycorynoline and m/z 380.2 → 243.2 for donepezil (internal standard), respectively. The calibration curves were linear (correlation coefficients > 0.9970) over the concentration ranges of 3.0-3000 pg/mL for corynoline and 3.0-1000 pg/mL for acetycorynoline. The established method was highly sensitive with the lower limit of quantification (LLOQ) of 3.0 pg/mL for both analytes. The intra- and inter-day precision was lower than 10% in terms of relative standard deviation for the low, medium, and high quality control samples, and lower than 16% for the LLOQ samples of the analytes. The accuracy was within ±10% in terms of relative error for both analytes. The method was successfully applied to a urinary excretion study after oral administration of the Chinese medicine formula Shuanghua Baihe tablets in healthy volunteers. The urinary excretion profiles of corynoline and acetycorynoline in human were first reported. The results of this study suggest that renal excretion was not the main excretion pathway of corynoline and acetycorynoline in humans. © 2016 Elsevier B.V. Source


Li Q.,China Pharmaceutical University | Wang Y.,Nanjing Clinical Technology Laboratories Inc. | Liu L.,China Pharmaceutical University | Ma P.,Peking Union Medical College | And 2 more authors.
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2016

Background and Objectives: Roflumilast is a selective, oral phosphodiesterase 4 inhibitor approved for the treatment of severe chronic obstructive pulmonary disease. The aim of this study was to evaluate the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy Chinese subjects, and the effects of gender and food on their respective pharmacokinetic profiles. Methods: 36 healthy Chinese subjects were recruited in a randomized, single-center, open-label, parallel group study and assigned to 0.25-, 0.375-, and 0.5-mg dose groups. The single-dose pharmacokinetic studies in fasting condition were carried out in all groups. Moreover, the food effect study and multiple-dose study were conducted in 0.375-mg dose group. Serial blood samples were collected over 168 h after dosing, and plasma concentrations of roflumilast and roflumilast N-oxide were determined using a validated LC-MS/MS method. Results: After oral administration of single doses of 0.25, 0.375 and 0.5 mg of roflumilast under fasting condition, the mean AUC0–72h for roflumilast was 21.7 ± 8.3, 29.8 ± 8.3 and 54.2 ± 21.3 ng·h/mL, respectively. Meanwhile the mean AUC0–168h for roflumilast N-oxide was 290 ± 103, 385 ± 107 and 673 ± 245 ng·h/mL, respectively. In the steady state after the multi-dose administration, the exposure to roflumilast in the subjects increased 20–40 %, and the exposure to roflumilast N-oxide increased about 169 %, compared to the single-dose administration. No statistically significant effect of gender on the disposition of roflumilast and roflumilast N-oxide was observed. Food had no effect on systemic exposure to roflumilast and roflumilast N-oxide in the subjects, but delayed the Tmax of roflumilast by 0.9 h and reduced the Cmax of roflumilast by approximately 20 %. Conclusion: Based upon between-study comparison, peak and systemic exposure of roflumilast and roflumilast N-oxide were higher in Chinese than that in Caucasian subjects after oral administration of the same dose (i.e., 0.25 and 0.5 mg). It implies that the therapeutic dose for Chinese patients may be different from that for Caucasians, warranting further investigation. © 2016 Springer International Publishing Switzerland Source


Liu R.,China Pharmaceutical University | Liu R.,Nanjing Clinical Technology Laboratories Inc. | Wu Y.,China Pharmaceutical University | Wu Y.,Nanjing Clinical Technology Laboratories Inc. | And 9 more authors.
RSC Advances | Year: 2015

Shuanghua Baihe tablets (SBT) are a traditional Chinese medicine formula which is used for treatment of oral mucositis (OM) for more than 30 years in China. So far, there has been no report of the quantification of the major components in SBT and their pharmacokinetics in humans. In this study, high performance liquid chromatography coupled to triple-quadrupole mass spectrometry was used to determine the content of the major compounds in SBT and to evaluate the pharmacokinetics of nine major constituents (berberine, epiberberine, coptisine, palmatine, jatrorrhizine, magnoflorine, berberrubine, corynoline and acetylcorynoline) following single and multiple oral administrations of SBT in healthy subjects. This study was an open-label and 2-period clinical trial. It was conducted in 12 Chinese healthy subjects. Each subject received a single dose in period 1 and multiple doses in period 2. Blood samples were collected and determined over 96 h. Subjects underwent safety assessments and were monitored for adverse events. There was no serious adverse event, death or withdrawal. Gender had a significant effect on the pharmacokinetics of the active alkaloids except for magnoflorine, berberrubine, corynoline and acetylcorynoline. Compared with the single dosing, the exposure of the alkaloids increased significantly except for berberrubine after multiple dosing. Single and multiple oral doses of SBT were safe in healthy Chinese subjects. The accumulation of the alkaloids to different extents was observed with repeated dosing except for berberrubine. This work provides useful information for clinical application in the treatment of OM, and a scientific basis for the study on the material foundation of the medicinal effectiveness of SBT and its mechanism of action. © The Royal Society of Chemistry. Source


Gu P.,China Pharmaceutical University | Gu P.,Nanjing Clinical Technology Laboratories Inc. | Liu R.-J.,China Pharmaceutical University | Liu R.-J.,Nanjing Clinical Technology Laboratories Inc. | And 9 more authors.
Chinese Journal of Natural Medicines | Year: 2016

An LC-MS/MS method was developed and validated for the simultaneous quantification of chlorogenic acid (CGA) and taurocholic acid (TCA) in human plasma using hydrochlorothiazide as the internal standard. The chromatographic separation was achieved on a Hedera ODS-2 column with a gradient elution using 10 mmol·L-1 of ammonium acetate buffer solution containing 0.5% of formic acid - acetonitrile as mobile phase at a flow rate of 300 μL·min-1. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring in negative ESI mode. The method was fully validated over the concentration ranges of 0.1-10 ng·mL-1 for CGA and 2-150 ng·mL-1 for TCA. It was successfully applied to a pharmacokinetic study of CGA and TCA in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets (SBTs). In the single-dose study, the maximum plasma concentration (Cmax), time to reach Cmax (Tmax) and elimination half-life (t1/2) of CGA were (0.763 8 ± 0.542 0) ng·mL-1, (1.0 ± 0.5) h, and (1.3 ± 0.6) h, respectively. In the multiple-dose study, the Cmax, Tmax and t1/2 of CGA were (0.663 7 ± 0.583 3) ng·mL-1, (1.1 ± 0.5) h, and (1.4 ± 0.7) h, respectively. For TCA, no significant characteristic increasing plasma TCA concentration-time curve was found in the volunteers after oral administration of SBTs, indicating its complicated process in vivo as an endogenous ingredient. © 2016 China Pharmaceutical University. Source


Cheng M.,China Pharmaceutical University | Cheng M.,Nanjing Clinical Technology Laboratories Inc. | Liu R.,China Pharmaceutical University | Liu R.,Nanjing Clinical Technology Laboratories Inc. | And 9 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2016

An LC-MS/MS method was developed and validated for the simultaneous determination of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine in human urine. The sample preparation procedure involved the four-fold dilution of the urine samples with acetonitrile/water (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 column under gradient elution at a flow rate of 0.4. mL/min with acetonitrile and water containing 0.5% formic acid as the mobile phase. The mass detection was performed in the positive mode. Calibration curves of the seven alkaloids showed good linearity (correlation coefficients. >. 0.9973) over their concentration ranges. To meet the requirements of urinary excretion study for each alkaloid in human, the lower limit of quantification was set at different values from 0.05063. ng/mL to 2.034. ng/mL for the seven alkaloids, respectively. The intra- and inter-batch precision and accuracy were all within ±15%. No matrix effect was observed for the analytes. The validated method was applied to the excretion study for the seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets. The average 72. h cumulative urinary excretion of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine accounted for 1.81%, 0.27%, 0.29%, 0.046%, 0.027%, 0.010% and 0.021% of the respective administered dose. © 2015 Elsevier B.V. Source

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