Effects of rainfall events on behavior of tetracycline antibiotics in a receiving river: Seasonal differences in dominant processes and mechanisms.

Tetracycline (TC) antibiotics are widely used in livestock and poultry breeding. However, limited work has been done on the partition of TCs between suspended sediment (SPS) and overlying water or on the seasonal effects of rainfall events on the behavior of TCs in receiving rivers. Here, we assessed the impacts of rainfall events in different seasons on the concentrations and fate of TCs in a typical watershed. Concentrations of TCs in river water, SPS, and surface sediment were determined before, during, and after rainfall events. Results indicated that the sequence of TC concentration levels in river water was wet season > normal season > dry season. Rainfall events in all seasons increased the concentrations of TCs in river water. The concentration of TCs in SPS reached 104 ng/g. The SPS concentrations were only 22-78 mg/L, while the daily fluxes of TCs in particulate form contributed 39%-62% of the total (dissolved and particulate) daily fluxes in river water. The increases in TCs in river water were mainly attributed to internal release from sediment during rainfall events in the dry season but to external input during rainfall events in the wet season. The degradation products of TCs with higher concentrations and greater toxicity than their parent compounds should be considered in the ecological risk assessment of TCs. This research demonstrated that manure application should not be conducted in the normal season or before rainfall events, especially heavy rainfall.

Determination of xanthotoxin using a liquid chromatography-mass spectrometry and its application to pharmacokinetics and tissue distribution model in rat.

A simple and selective liquid chromatography mass spectrometry method for determination of xanthotoxin in rat plasma and various tissues for pharmacokinetic was developed. Chromatographic separation was achieved on a C18 (2.1 mm × 150 mm, 5 µm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used for quantification using target fragment ions m/z 217 for xanthotoxin and m/z 326 for the internal standard. The resulting calibration curves offered satisfactory linearity (R(2) > 0.99) within the test range. Mean recoveries of xanthotoxin in rat plasma were in the range of 79.9%-84.6%. RSD of intra-day and inter-day precision were both < 14%. The accuracy of the method ranged from 87.5% to 109.8%. The assay was successfully applied to the pharmacokinetics and tissue distribution model studies of xanthotoxin in rats. The oral bioavailability of xanthotoxin was 73.2% in rats.

The Effect of MGCD0103 on CYP450 Isoforms Activity of Rats by Cocktail Method.

MGCD0103, an isotype-selective histone deacetylase inhibitor (HDACi), has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In order to investigate the effects of MGCD0103 on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of human CYP2B1, CYP1A2, CYP2C11, CYP2D6, CYP3A4, and CYP2C9. The rats were randomly divided into MGCD0103 group (Low, Medium, and High) and control group. The MGCD0103 group rats were given 20, 40, and 80 mg/kg (Low, Medium, and High) MGCD0103 by continuous intragastric administration for 7 days. Six probe drugs, bupropion, phenacetin, tolbutamide, metoprolol, testosterone, and omeprazole, were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for tolbutamide in rats were observed by comparing MGCD0103 group with control group. Continuous 7-day intragastric administration of MGCD0103 slightly induces the activities of CYP2C11 of rats.

Effect of Radix Sophorae Tonkinensis on the activity of cytochrome P450 isoforms in rats.

Radix Sophorae Tonkinensis (S. tonkinensis) is the processed lateral root of Sophora subprostrata (Leguminosae) that widely distributed over the southwest China. Radix Sophorae Tonkinensis has been widely used as a Chinese medicinal herb for the treatment of disease such as jaundice, inflammation, and aches. Herein, in order to investigate the effects of Radix Sophorae Tonkinensis on the metabolic capacity of rat cytochrome P450 (CYP) enzymes, we employed a cocktail method to evaluate the activities of CYP1A2, CYP2D6, CYP3A4, CYP2C19, CYP2C9 and CYP2B6. The experimental rats were randomly divided into two groups (control group and Radix Sophorae Tonkinensis treated group). The Radix Sophorae Tonkinensis treated group rats were given 5 g/kg Radix Sophorae Tonkinensis by continuous intragastric administration for 14 days. The mixture of six probes (phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion) was given to rats by intragastric administration. The concentrations of probe drugs in rat plasma were measured by UPLC-MS/MS. The results showed that continuous intragastric administration for 14 days may inhibit the activities of rat CYP450 isoforms CYP2D6, CYP2C19 and CYP2B6. This finding may provide guidance for rational clinical uses of Radix Sophorae Tonkinensis.

Effect of Radix Sophorae Flavescentis on activity of CYP450 isoforms in rats.

Kushen (Radix Sophorae Flavescentis) is the dried roots of Sophora Flavescens Ait, alkaloids and flavonoids are the main active constituents of Radix Sophorae Flavescentis. The influence of Radix Sophorae Flavescentis on the activities of CYP450 isoforms CYP2B6, CYP2C19, CYP1A2, CYP2C9, CYP3A4 and CYP2D6 were evaluated by cocktail method. The rats were randomly divided into Radix Sophorae Flavescentis group and control group. The Radix Sophorae Flavescentis group rats were given 5 g/kg Radix Sophorae Flavescentis decoction by intragastric administration. The six probe drugs (bupropion, omeprazole, phenacetin, tolbutamide, midazolam and metroprolol) were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of Radix Sophorae Flavescentis group compared to control group, there were statistical pharmacokinetics difference for omeprazole, phenacetin, tolbutamide and metroprolol. It indicated that the Radix Sophorae Flavescentis may induce the activities of CYP2D6, and inhibit of CYP2C19, CYP1A2 and CYP2C9 of rats. As other drugs are always used after Radix Sophorae Flavescentis, interactions between other drugs and Radix Sophorae Flavescentis undertake the risk of either diminished efficacy or adverse effects. This may give advising for reasonable drug use after Radix Sophorae Flavescentis.

Effect of diphenoxylate on CYP450 isoforms activity in rats.

In order to investigate the effects of diphenoxylate on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B6, CYP2D6, CYP2C19, CYP1A2, CYP3A4, CYP2C9. The rats were randomly divided into diphenoxylate group (Low, Medium, High) and control group. The diphenoxylate group rats were given 12, 24, 48 mg/kg (Low, Medium, High) diphenoxylate by continuous intragastric administration for 7 days. Six probe drugs bupropion, metroprolol omeprazole, phenacetin, testosterone and tolbutamide were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for omeprazole, phenacetin and tolbutamide in rats were observed by comparing diphenoxylate group with control group. Continuous 7 days-intragastric administration of diphenoxylate induces the activities of CYP2C19, CYP1A2 and CYP2C9 of rats. Induction of drug metabolizing enzyme by diphenoxylate would reduce the efficacy of other drug. Additionally, high dosage diphenoxylate may cause hepatotoxicity.

Liquid chromatography mass spectrometry simultaneous determination of vindoline and catharanthine in rat plasma and its application to a pharmacokinetic study.

Vinblastine and vincristine, both of which are bisindole alkaloids derived from vindoline and catharanthine, have been used for cancer chemotherapy; their monomeric precursor molecules are vindoline and catharanthine. A simple and selective liquid chromatography mass spectrometry method for simultaneous determination of vindoline and catharanthine in rat plasma was developed. Chromatographic separation was achieved on a C18 (2.1 × 50 mm, 3.5 µm) column with acetonitrile-0.1% formic acid in water as mobile phase with gradient elution. The flow rate was set at 0.4 mL/min. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification. Mean recoveries were in the range of 87.3-92.6% for vindoline in rat plasma and 88.5-96.5% for catharanthine. Matrix effects for vindoline and catharanthine were measured to be between 95.3 and 104.7%. Coefficients of variation of intra-day and inter-day precision were both <15%. The accuracy of the method ranged from 93.8 to 108.1%. The method was successfully applied in a pharmacokinetic study of vindoline and catharanthine in rats. The bioavailability of vindoline and catharanthine were 5.4 and 4.7%, respectively.

Development of LC-MS determination method and back-propagation ANN pharmacokinetic model of corynoxeine in rat.

Corynoxeine(CX), isolated from the extract of Uncaria rhynchophylla, is a useful and prospective compound in the prevention and treatment for vascular diseases. A simple and selective liquid chromatography mass spectrometry (LC-MS) method was developed to determine the concentration of CX in rat plasma. The chromatographic separation was achieved on a Zorbax SB-C18 (2.1 mm × 150 mm, 5 µm) column with acetonitrile-0.1% formic acid in water as mobile phase. Selective ion monitoring (SIM) mode was used for quantification using target ions m/z 383 for CX and m/z 237 for the carbamazepine (IS). After the LC-MS method was validated, it was applied to a back-propagation artificial neural network (BP-ANN) pharmacokinetic model study of CX in rats. The results showed that after intravenous administration of CX, it was mainly distributed in blood and eliminated quickly, t1/2 was less than 1h. The predicted concentrations generated by BP-ANN model had a high correlation coefficient (R>0.99) with experimental values. The developed BP-ANN pharmacokinetic model can be used to predict the concentration of CX in rats.

Gradient elution liquid chromatography mass spectrometry determination of acetylcorynoline in rat plasma and its application to a pharmacokinetic study.

1. Acetylcorynoline is the major alkaloid component derived from Corydalis bungeana herbs. A sensitive and selective liquid chromatography mass spectrometry method for determination of acetylcorynoline in rat plasma was developed over the range of 5-1000 ng/mL to characterize the pharmacokinetic properties. 2. Chromatographic separation was achieved on a C18 (2.1 mm× 150 mm, 5 µm) column with acetonitrile 0.1% formic acid in water as mobile phase with gradient elution. The flow rate was set at 0.4 mL/min. After addition of carbamazepine as internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used as sample preparation. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification using target ions m/z 410 for acetylcorynoline and m/z 237 for the IS. 3. Mean recoveries of acetylcorynoline in rat plasma were in the range of 72.3-87.6%. Matrix effects for acetylcorynoline were measured to be between 88.7% and 93.5%. Coefficient of variation of intra-day and inter-day precision were both <13%. The accuracy of the method ranged from 95.8% to 112.1%. The analyte was stable under auto-sampler, room temperature, freeze-thaw and long-term (20 days), the bias in concentration was within ±15% of their nominal values. 4. The LC-MS method for the determination of acetylcorynoline in rat plasma utilizing 100 µL of plasma with an LLOQ of 5.0 ng/mL developed and validated, it was sensitive, selective and simple. This method was successfully applied in pharmacokinetic study of acetylcorynoline after intravenous administration of single dosage 3 mg/kg in rats.

Determination of rhynchophylline in rat plasma by liquid chromatography mass spectrometry and its application.

A sensitive and selective liquid chromatography mass spectrometry method was developed for the determination of rhynchophylline in rat plasma. After the addition of estazolam as the internal standard (IS), protein precipitation by acetonitrile was used for sample preparation. Chromatographic separation was achieved on a Zorbax SB-C18 column (2.1 × 150 mm, 5 µm) with acetonitrile-0.1% formic acid as the mobile phase with gradient elution. The electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification by using target fragment ions m/z 385 for rhynchophylline and m/z 295 for the IS. Calibration plots were linear over the range of 5-500 ng/mL for rhynchophylline in plasma. The lower limit of quantification for rhynchophylline was 5 ng/mL. The mean recovery of rhynchophylline from plasma was in the range of 87.7-92.6%. The coefficients of variation of intra-day and inter-day precision were both less than 11%. This method is sensitive and selective enough to be used in pharmacokinetic research for the determination of rhynchophylline in rat plasma.

Simultaneous determination of evodiamine and rutecarpine in rabbit plasma by LC-ESI-MS and its application to pharmacokinetics.

A sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method for the determination of evodiamine and rutecarpine in rabbit plasma was developed and validated. The analytes and internal standard (IS) are extracted from plasma by one-step protein precipitation with acetonitrile, and separated on a Zorbax SB-C18 column (2.1 mm x 50 mm, 3.5 microm) using acetonitrile-0.1% formic acid as mobile phase with gradient elution. Electrospray ionization (ESI) source was applied and operated in positive ion mode, and selective ion monitoring (SIM) mode used to quantify evodiamine and rutecarpine. The assay is linear over the range of 2-1600 ng/mL for evodiamine and rutecarpine, with a lower limit of quantification (LLOQ) of 5 ng/mL both for evodiamine and rutecarpine. Intra-day and inter-day precision are less than 12% and the accuracy are in the range of 90.9-104.3%. Furthermore, the newly developed method is successfully used for the determination of evodiamine and rutecarpine in rabbit plasma for pharmacokinetic study.