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Aim:To evaluate the pharmacokinetic interactions between theophylline and antofloxacin in vivo and in vitro.Methods:A randomized, 5-day treatment and 3-way crossover design was documented in 12 healthy subjects. The subjects were orally administered with antofloxacin (400 mg on d 1 and 200 mg on d 2 to 5), theophylline (100 mg twice a day and morning dose 200 mg on d 1 and 5), or theophylline plus antofloxacin. The plasma and urinary pharmacokinetics of antofloxacin and theophylline were characterized after the first and last dose. The effect of antofloxacin on theophylline metabolism was also investigated in pooled human liver microsomes.Results:The 5-day treatment with antofloxacin significantly increased the area of the plasma concentration-time curve and peak plasma concentration of theophylline, accompanied by a decrease in the excretion of theophylline metabolites. On the contrary, theophylline did not affect the pharmacokinetics of antofloxacin. In vitro studies using pooled human hepatic microsomes demonstrated that antofloxacin was a weak reversible and mechanism-based inhibitor of CYP1A2. The clinical interaction between theophylline and antofloxacin was further validated by the in vitro results.Conclusion:The results showed that antofloxacin increases the plasma theophylline concentration, partly by acting as a mechanism-based inhibitor of CYP1A2. [ABSTRACT FROM AUTHOR]

Abstract: Otilonium bromide (OB) degrades rapidly in plasma and readily undergoes hydrolysis by the plasma esterase. In this paper, an LC–ESI-MS method has been developed for the determination of OB in human plasma. The rapid degradation of OB in plasma was well prevented by immediate addition of potassium fluoride (KF, an inhibitor of plasma esterase) to the freshly collected plasma before prompt treatment with acetonitrile. The method was validated over the concentration range of 0.1–20ng/ml. The data of intra-run and inter-run precision and accuracy were within ±15%. The mean extraction recoveries for OB and the internal standard were higher than 93.0% and the matrix effects were negligible. The method has been successfully used in a pharmacokinetic study. [ABSTRACT FROM AUTHOR]

Purpose Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme ( CYP2C19 ) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. Methods Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry. Findings There were no significant differences in C max and AUC 0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM C max value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [ P  = 0.003] and 19.55 [2.19] ng/mL [ P  = 0.004], respectively). The mean CAM AUC 0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [ P  = 0.007] and 27.08 [2.72] ng · h/mL [ P  = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group ( P  = 0.001). The correlations between the pharmacokinetic properties (C max , AUC 0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P < 0.01). Implication In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382. [ABSTRACT FROM AUTHOR]

Abstract: A liquid chromatography–electrospray ionization tandem mass spectrometry (HPLC–ESI-MS/MS) method for the determination of andrographolide in human plasma was established. Dehydroandrographolide was used as the internal standard (I.S.). The plasma samples were deproteinized with methanol and separated on a Hanbon C18 column with a mobile phase of methanol–water (70:30, v/v). HPLC–ESI-MS/MS was performed in the selected ion monitoring (SIM) mode using target ions at [M−H2O–H]−, m/z 331.1 for andrographolide and [M−H]−, m/z 331.1 for the I.S. Calibration curve was linear over the range of 1.0–150.0ng/mL. The chromatographic separation was achieved in less than 6.5min. The lower limits of quantification (LLOQ) was 1.0ng/mL. The intra and inter-run precisions were less than 6.95 and 7.22%, respectively. The method was successfully applied to determine the plasma concentrations of andrographolide in Chinese volunteers. [Copyright &y& Elsevier]

Abstract: This study presents a high-performance liquid chromatography–positive/negative electrospray ionization tandem mass spectrometric (LC–ESI(+/−)–MS–MS) method for the determination of betamethasone (BOH) and betamethasone 17-monopropionate (B17P) in human plasma using beclomethasone dipropionate as the internal standard (I.S.). Both compounds were extracted from human plasma with ether–cyclohexane (4:1, v/v) and were separated by HPLC on a Hanbon Lichrospher C18 column with a mobile phase of methanol–water (85:15, v/v) at a flow rate of 0.7ml/min. Calibration curves were linear over the range of 0.10–50ng/ml for BOH and 0.050–50ng/ml for B17P. The inter-run relative standard deviations were less than 14.4% for BOH and 12.3% for B17P. The intra-run relative standard deviations were less than 9.3% for BOH and 7.9% for B17P. The mean plasma extraction recovery for BOH and B17P were in the ranges of 82.7–85.9% and 83.6–85.3%, respectively. The method was successfully applied to study the pharmacokinetics of a new formulation of betamethasone phosphate/betamethasone dipropionate injection in healthy Chinese volunteers. [Copyright &y& Elsevier]

Abstract: A simple, rapid and sensitive high performance liquid chromatography–electrospray ionization-tandem mass spectrometry (HPLC–ESI-MS/MS) assay for determination of tegaserod in human plasma using diazepam as internal standard (IS) was established. After adjustment to a basic pH with sodium hydroxide, plasma was extracted by ethyl acetate and separated by high performance liquid chromatography (HPLC) on a reversed-phase C18 column with a mobile phase of methanol: 5mM ammonium acetate (75:25, v/v, adjusting the pH to 3.5 with glacial acetic acid). The quantification of target compounds was obtained by using multiple reaction monitoring (MRM) transitions; m/z 302.5, 173.2 and 285.4, 193.2 were measured in positive mode for tegaserod and internal standard (diazepam), respectively. The lower limit of quantification (LLOQ) was 0.05ng/ml. The calibration curves were linear over the range 0.05–8.0ng/ml (r =0.9996) for tegaserod. The mean absolute recovery of tegaserod was more than 85.56%. Intra- and inter-day variability values were less than 9.21% and 10.02%, respectively. The samples were stable for 8h under room temperature (25°C, three freeze–thaw cycles in 30 days and for 30 days under −70°C). After administration of a single dose of tegaserod maleate 4mg, 6mg and 12mg, respectively, the area under the plasma concentration versus time curve from time 0h to 12h (AUC0–12) were (2.89±0.88), (5.32±1.21) and (9.38±3.42) ngh/ml, respectively; peak plasma concentration (C max) were (1.25±0.53), (2.21±0.52) and (4.34±1.66) ng/ml, respectively; apparent volume of distribution (V d /F) were (6630.5±2057.8), (7615.2±2242.8) and (7163.7±2057.2) l, respectively; clearance rate (CL/F) were (1851.4±496.9), (1596.2±378.5) and (1894.2±459.3) l/h, respectively; time to C max (T max) were (1.00±0.21), (1.05±0.28) and (1.04±0.16) h, respectively; and elimination half-life (t 1/2) were (3.11±0.78), (3.93±0.92) and (3.47±0.53) h, respectively; MRT were (3.74±0.85), (4.04±0.56) and (3.28±0.66) h, respectively. The essential pharmacokinetic parameters after oral multiple doses (6mg, b.i.d) were as follows: C ssmax, (2.72±0.61) ng/ml; T max, (1.10±0.25) h; C ssmin, (0.085±0.01) ng/ml; C av, (0.54±0.12) ng/ml; DF, (4.84±0.86); AUCss, (6.53±1.5) ngh/ml. This developed and validated assay method had been successfully applied to a pharmacokinetic study after oral administration of tegaserod maleate in healthy Chinese volunteers at a single dose of 4mg, 6mg and 12mg, respectively. The pharmacokinetic parameters can provide some information for clinical medication. [Copyright &y& Elsevier]