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Fuzheng Huayu recipe (FZHY) combined with entecavir (ETV) is used to treat the cirrhosis caused by chronic hepatitis B (CHB) infection. To investigate the effect of FZHY on ETV pharmacokinetics under different conditions. A model of liver fibrosis was created by intraperitoneal injection of dimethylnitrosamine (DMN; 10 μg/kg) for 4 weeks in Wistar rats. Ultra-high-performance liquid chromatography–tandem mass spectrometry was used to determine the blood concentration of ETV. Pharmacokinetic characteristics of ETV (0.9 mg/kg) were investigated after co-administration with FZHY (0.55 g/kg) at certain time intervals in normal and model rats. The analytical method for ETV was validated at 0.5–50 μg/L with a correlation coefficient = 0.9996, lower limit of quantitation of 0.5 μg/L and mean accuracy of 104.18 ± 9.46%. Compared with the ETV-N group, the pharmacokinetic parameters of the EF-2 group did not change significantly, but that of the EF-0 group decreased in Cmax to 27.38 μg/L, in AUC0–t from 323.84 to 236.67 μg/h/L, and a delay in Tmax from 0.75 to 6.00 h; that of the EF-0 group presented a decrease in Cmax of 61.92%, delay in t1/2 of 2.45 h and delay in Tmax of 2.92 h. The t1/2e and Vd/F of ETV were increased significantly to 8.01 h and 24.38 L/kg in the ETV-M group. The effects of FZHY on ETV pharmacokinetics were diminished with an increase of interval time. The best time to administer both drugs is >2 h apart. [ABSTRACT FROM AUTHOR]

Development of prodrug of 9-hydroxyrisperidone (paliperidone) long-acting intramuscular injection has enabled delivery over four-week time period with improved compliance. The key aim of this work was to establish a reliable preclinical model which may potentially serve as a screening tool for judging the pharmacokinetics of paliperidone formulation(s) prior to human clinical work. Sparse sampling composite study was used in rats, (Wistar/Sprague-Dawley (SD; n = 10)) and a serial blood sampling study design was used in rabbits (n = 4). Animals received intramuscular injection of paliperidone palmitate in the thigh muscle at dose of 16 (rats) and 4.5 mg/kg (rabbits). Samples were drawn in rats (retro-orbital sinus) and rabbits (central ear artery) and were analysed for paliperidone using liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS) assay. The plasma data was subjected to pharmacokinetic analysis. Following intramuscular injection of depot formulation in Wistar/SD rats and rabbits, absorption of paliperidone was slow and gradual with median value of time to reach maximum concentration (Tmax) occurring on day 7. The exposures (i.e. area under the curve (AUC; 0-28) days) were 18,597, 21,865 and 18,120 ng.h/mL, in Wistar, SD and rabbits, respectively. The clearance was slow and supported long half-life (8-10 days). Either one of the two models can serve as a research tool for establishing pharmacokinetics of paliperidone formulation(s). [ABSTRACT FROM AUTHOR]

Isocorynoxeine (ICOR) is one of the bioactive oxindole alkaloids inUncariaspecies. This study presents the pharmacokinetics and mass balance of ICOR in rats after oral dose of 40.0 mg/kg and intravenous dose of 4.0 mg/kg through detection of ICOR and its in vivo metabolites, using an optimized LC-MS with recoveries ranged from 94 to 104%, accuracy varied from 96 to 103%, and relative standard deviation for assay being less than 5%. ICOR reached its Cmaxof 336.7 ng/mL in plasma 3 hr after oral dose. The phase I metabolites of ICOR, 11-hydroxyisocorynoxeine (M1), and 10-hydroxyisocorynoxeine (M2) were detected in rat heart, kidneys, urine, and feces; whereas, in rat liver and bile, M1, M2, along with phase II metabolites, 11-hydroxyisocorynoxeine 11-O-β-D-glucuronide, and 10-hydroxyisocorynoxeine 10-O-β-D-glucuronide were identified. ICOR (77.0%) was excreted into feces and urine after oral administration within 72 hr, 0.93% drained into bile in 8 hr, 17.9% biotransformed into M1 and M2 at a ratio ofca. 1:1, and 0.028% detected in main organs attmax, in which brain uptake index is 3.2 ng/g. This work affords a developed and validated LC-MS for simultaneous determination of ICOR and itsin vivometabolites with improved precision and accuracy. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

A sensitive and selective liquid chromatography mass spectrometry (LC–MS) method for determination of isocorynoxeine in rat plasma was developed. After addition of midazolam as internal standard (IS), sample preparation was performed by using liquid–liquid extraction with ethyl acetate. Chromatographic separation was achieved on a Zorbax SB-C18 (2.1 mm × 150 mm, 5 µm) column with acetonitrile-0.1% formic acid as mobile phase with gradient elution. Electrospray ionization (ESI) source was applied and operated in positive ion mode; selective ion monitoring (SIM) mode was used to quantify using target fragment ionsm/z383 for isocorynoxeine andm/z326 for the IS. Calibration plots were linear over the range of 5–500 ng/mL for isocorynoxeine in plasma. Lower limit of quantification (LLOQ) for isocorynoxeine was 5 ng/mL. Mean recovery of isocorynoxeine from plasma was in the range of 93.6–96.6%. CV of intra-day and inter-day precision were both less than 15%. The newly developed method is simple, sensitive, and could function effectively in pharmacokinetic characterization of isocorynoxeine in rat plasma. [ABSTRACT FROM PUBLISHER]

A sensitive and simple liquid chromatography/electrospray mass spectrometry (LC-ESI-MS) method for determination of diphenoxylate in rat plasma using one-step protein precipitation was developed and validated. After addition of estazolam as internal standard (IS), protein precipitation by acetonitrile was used as sample preparation. Chromatographically separation was achieved on an SB-C18 (2.1 mm × 50 mm, 3.5 µm) column with acetonitrile-0.1% formic acid as the mobile phase with gradient elution. Electrospray ionization (ESI) source was applied and operated in positive ion mode; selected ion monitoring (SIM) mode was used to quantification using target fragment ionsm/z453.1 for diphenoxylate andm/z294.8 for the IS. Calibration plots were linear over the range of 5–1000 ng/mL for diphenoxylate in rat plasma. Lower limit of quantification (LLOQ) for diphenoxylate was 5 ng/mL. Mean recovery of diphenoxylate from plasma was in the range of 96.69–98.27%. RSD of intra-day and inter-day precision were both less than 9%. This method is simple and sensitive enough to be used in pharmacokinetic research for determination of diphenoxylate in rat plasma. [ABSTRACT FROM AUTHOR]

A highly selective and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of scicinib, a novel thiosemicarbazone analogue and anticancer agent in rat plasma. Protein precipitation with saturated EDTA solution and methanol was selected for sample preparation, and brodimoprim was employed as the internal standard (IS). The analytes were separated on a Symmetry C18column (200 × 4.6 mm i.d., 5 µm) by isocratic elution with a mobile phase consisting of methanol and 0.2 mM EDTA (75:25, v/v) at a flow rate of 0.4 mL/min. After electrospray ionization, the analyte and IS were recorded under selected reaction monitoring (SRM) mode. The chosen transition wasm/z313.0 → 267.9 for scicinib andm/z339.0 → 280.9 for IS, respectively. The validated linearity range is 5–5000 ng/mL, with the lower limit of quantitation of 5 ng/mL. The developed method was successfully applied to a pharmacokinetic study of scicinib in rats after a single intravenous administration of 5 mg/kg. [ABSTRACT FROM AUTHOR]

This study was designed to get the direct evidence of the autoinduction metabolism for the antimalarial drug artemisinin (QHS). The sex effect on the pharmacokinetic profiles of QHS and its metabolites was also studied. Two groups of rats received a single oral dose of QHS, and another two groups of rats were given oral doses of QHS once daily for 5 consecutive days. Plasma samples and its phase I and phase II metabolites were analysed for QHS, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method. Eight phase I metabolites (DQHS, M1–M7) and five phase II metabolites (M8–M12) of QHS were detected in rat plasma. The AUC0−t of the parent drug QHS, and its phase I metabolites DQHS, M2, M3 and M6 decreased significantly (p < 0.05) with increased oral clearance (CL/F) (p < 0.05) after 5-day oral doses of QHS to rats. There was no change (p > 0.05) in AUC of M1 and M4, whereas its metabolites M5 and M7 exhibited higher AUC (p < 0.05). The AUC of phase II metabolites M8, M11 and M12 also increased after multiple oral doses of QHS. Sex difference was observed for QHS and its metabolites DQHS, M1, M3, M5, M8 and M9 in rats after a single oral dose of QHS. The results gave the direct evidence for the autoinduction of both phase I and phase II metabolism of QHS. The sex effect existed for QHS. [ABSTRACT FROM AUTHOR]

A simple and rapid liquid chromatography-tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the quantitation of indirubin-5-nitro-3′-monoxime (5-NIO) in rat plasma using 5-chloro-5′-chloro-indirubinoxime as the internal standard. The sample preparation involved protein precipitation using acetonitrile. Separation was achieved on an Xterra column C18 (2.1 mm × 50 mm, i.d. 5 µm) using a mixture of 0.1% formic acid-water/acetonitrile (18:82, v/v) as the mobile phase at a flow rate of 300 µL/min. Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization and multiple reaction monitoring (MRM) in negative ion mode. The total chromatographic run time was 2.5 min, and the calibration curves of 5-NIO were linear (correlation coefficient range: 0.9989–0.9999) over the concentration range of 0.2–2000 ng/mL in rat plasma. Also, the detection limit of the method was 0.05 ng/mL and it showed good accuracy and precision within the concentration range of 0.45–376 ng/mL. This validated method was successfully applied to estimating the pharmacokinetic parameters of 5-NIO following intravenous administration of 5-NIO to rats. [ABSTRACT FROM AUTHOR]

A simple and specific LC-MS/MS method for the determination of FK506 in blood was developed, validated, and successfully applied in pharmacokinetic studies of the effect of silymarin on FK506 in rats. Blood samples were extracted by liquid-liguid extraction with methyl tert-butyl ether and separated on an Eclipse plus-C18 column (150 × 2.1 mm, 3.5 µm) with the mobile phase of acetonitrile-10 mM ammonium acetate buffer solution (80:20, v/v). FK506 was detected without interference in the multiple-reaction monitoring mode with positive electrospray ionization. Good linearity was achieved over a range of 2.0–200 ng mL−1. The intra- and inter-day precisions were less than 13.5 % for all concentrations of quality control samples. The recoveries of FK506 were 74.2–85.3 %. Although the mean Cmax and AUC0 − ∞ of FK506 were increased to some extent, there was no significant difference in the pharmacokinetic profile of FK506 after oral administration to rats in the presence and absence of silymarin (200 mg kg−1, 2 times/d for 14 d). [ABSTRACT FROM AUTHOR]

To evaluate the bioavailability of exemestane (EXM) from self-micro emulsifying drug delivery systems (SMEDDS) and suspension formulations, a sensitive, specific, and rapid liquid chromatography-mass spectrometric method was developed and validated. The analyte was extracted from plasma samples and detected by mass spectrometry (MS) with an atmospheric pressure positive-ion chemical ionization (APCI) mode using a heated nebulizer interface. Progesterone (PGS) was used as the internal standard. A Hychrome RPB-L428 column was used to perform the chromatographic separation, the mobile phase being methanol and 15 mM ammonium formate (80:20). The MS detection used a heated nebulizer interface, with multiple reaction monitoring (MRM) operated in positive-ion mode. Both, EXM and PGS were well-separated and identified by their relative retention times, that is, 1.13 and 1.84 min, respectively. After oral administration of EXM loaded SMEDDS and suspension formulation to rats, a significant difference was observed in the pharmacokinetic behavior of drug in both the formulations, and a 2.9-fold increase in the relative bioavailability of EXM was observed with the SMEDDS as compared with suspension formulation. The developed method was found to be suitable for bioanalysis of exemestane and, hence, successfully depicted the bioavailability enhancement of exemestane SMEDDS in Wistar rats. [ABSTRACT FROM AUTHOR]

A rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry method was developed and validated for the determination and quantification of ephedrine in rat plasma samples. An Acquity UPLC BEH C18 column (1.7 μm, 2.1 mm × 50 mm) was used for chromatographic separation. Electrospray ionization in the positive mode was used, and the precursor-fragment ion pairs of m/z 166/148 and m/z 289/97 were adopted to characterize ephedrine and testosterone (internal standard), respectively. The method was validated using 10, 100 and 500 ng/mL of ephedrine. It demonstrated adequate levels of precision and accuracy, matrix effect, extraction recovery and stability. Linearity over the concentration range of 0.5–2000 ng/mL was acceptable with a correlation coefficient (r2) better than 0.990. To determine the pharmacokinetic behaviour of this sympathomimetic compound in the Sprague-Dawley rats, ephedrine hydrochloride, Herba Ephedrae single-herb and Wu Tou Tang decoctions were administered orally, and ephedrine hydrochloride was also administered by intravenous injection, and blood samples were collected over 24 h. Ephedrine was measured in plasma and pharmacokinetic parameters were determined by using the standard non-compartmental method and calculated by using Practical Pharmacokinetic Program-Version 87/97. The AUC(0–t) and Tmax values were significantly different (p < 0.05). Ephedrine AUC(0–t) values were significantly lower following the Wu Tou Tang decoction compared to the other oral treatments, suggesting that some components in the decoction may reduce the bioavailability of ephedrine [ABSTRACT FROM AUTHOR]

A sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method for determination of tolbutamide and its metabolite hydroxytolbutamide in rat plasma was developed and validated. The analytes and internal standard omeprazole were extracted from plasma by liquid-liquid extraction using ethyl acetate, and chromatographically separated on a Zorbax SB-C18 column (2.1 mm × 50 mm, 3.5 µm) using acetonitrile-0.1% formic acid as the mobile phase with gradient elution. Electrospray ionization (ESI) source was applied and operated in positive ion mode, and selected ion monitoring (SIM) mode used to quantify tolbutamide and its metabolite hydroxytolbutamide. The assay was linear over the range 10–20000 ng/mL for tolbutamide and 5–800 ng/mL for hydroxytolbutamide, with a lower limit of quantification (LLOQ) of 10 ng/mL for tolbutamide and 5 ng/mL for hydroxytolbutamide. Intra- and inter-day precision were less than 12% and the accuracy were in the range 88.8–109.7%. This developed method was successfully used for determination of tolbutamide and metabolite hydroxytolbutamide in rat plasma for pharmacokinetic study. [ABSTRACT FROM AUTHOR]