Dissertation > Excellent graduate degree dissertation topics show

The chiral separation of the two drugs , stereoselective pharmacokinetic studies

Author: LuXiuMei
Tutor: LiFaMei
School: Shenyang Pharmaceutical University
Course: Pharmaceutical Analysis
Keywords: simendan mabuterol chiral separation stereoselective pharmacokinetics capillary electrophoresis
CLC: R96
Type: Master's thesis
Year: 2005
Downloads: 146
Quote: 0
Read: Download Dissertation

Abstract


Enantioseparation of chiral compound is the foundation of new chiral drug’s research and development. Searching for high efficient, sensitive, rapid and simple chiral separation method in laboratory is important in pharmaceutical analysis field. Chiral separation of simendan and mabuterol was investigated in the present work by using high performance capillary electrophoresis （HPCE） and high performance liquid chromatography （HPLC）. The pharmacokinetics of mabuterol enantiomers in rats were also studied by using the developed HPLC method.1. Chiral separation of simendan enantiomers by capillary zone electrophoresisThe enantiomers of simendan were separated by capillary zone electrophoresis （CZE） usingβ-cyclodextrin （β-CD） as the chiral selector. The influences of the concentration and pH of borate buffer solution,β-CD concentration, methanol content and separation voltage were investigated. A baseline separation of simendan enantiomers was achieved with background electrolyte of 20mmol/L borate buffer （pH 11.0） containing 12mmol/Lβ-CD-methanol （50:50, v/v） at a voltage of 20 kV.2. Determination of the dissociation constant （pKa） value of mabuterol by capillary electrophoresisKnowledge of dissociation constant is important for prediction and understanding of the migration behavior of analytes in capillary electrophoresis. A CZE method was used to determine the pKa value of mabuterol based on the linear relation between the reciprocal ofeffective mobility of the solute （1/μe） and the reciprocal of [H+] of the buffer solution. Acetoneof 1% was chosen as the neutral marker. The running buffer was sodium phosphate with different pH with same ion strength of 0.09. The UV detector was set at 254nm; electrophoresis was performed at a voltage of 10 kV. The dissociation constant was determined to be 10.14, which was similar with that of comparative method （Iso-molarity UV spctrophotometry）. Based on this result, chiral separation of mabuterol was investigated by HPCE.3. The simultaneous enantiomeric separation of mabuterol and its analogue by HPCE The capillary electrophoretic separation of four adrenergicβ2-agonist （mabuterol,clenbuterol, SPFF, bambuterol） enantiomers were studied with Hydroxypropyl-β-cyclodextrin （HP-β-CD） as chiral selector. The effects of buffer pH and concentration of HP-β-CD on the electrophoretic resolution were investigated. Separation conditions were optimized to be: 100mmol/L citric acid-10mmol/L Na2HPO4-120mmol/L HP-β-CD buffer solution （pH 2.5）, applied voltage of 20kV, detection at 210nm. Four adrenergicβ2-agonist enantiomers were satisfactorily separated simultaneously under this condition. The methodology was investigated and this method was used in the determination of enantiomeric purity of SPFF and mabuterol.4. Analysis of enantiomers in vivo and stereoselective pharmacokinetics of mabuterol in ratsAn achiral-chiral sequential method to determine the enantiomers of mabuterol in rat plasma was developed. Mabuteol was separated with endogenesis substances in plasma earlier by achiral chromatography system. Then the fraction of mabuterol from the achiral system was collected. The two enantiomers of mabuterol were separated by the chiral chromatography system, which was composed of Chirobiotic V column and mobile phase of MeOH-HAc-TEA （100/0.01/0.01, v/v/v）. Based on the concentration of mabuterol and the l/d ratios in the same sample, the plasma levels for l-and d-mabuterol were calculated. The method described above was used for the stereoselective pharmacokinetics study of mabuterol in six Wistar rats after intra gastric administraiton of 10mg/kg mabuterol racemate. The results showed that both enantiomers were absorbed slowly with a similar tmax of 5.33±2.1h and 5.67±1.51, and Cmax, of 266.8±37.9ng/ml and 277.9±44.6ng/ml for l-mabuteol and d-mabuteol, respectively （p＞0.05）. Significant differences of AUC0-∞、t1／2（k）、CL/F and MRT were found between two enantiomers of mabuterol by paired Student’s t-test, which indicated that l-mabuterol was more effective and persisting longer than its antipode, showed the metabolic stereoselectivity of mabuterol. The developed method should be fundamental contributions for the preclinical study of single mabuterol enantiomer.

Related Dissertations

  1. Synthesis and Resolution Property of N-(9-Fluorenylmethoxycarbonyl)-D-Tryptophan and D-Phenylalanine Imprinted Polymer,O631.3
  2. Immobilized Lactobacillus Fermentation L-Lactic Acid Study and Application,TQ921.3
  3. Combination Degradation of Chlor Pyrifos Via Biodegradation and Photodegradation,X592
  4. The Isolation, Identification and Quantification of Flavonoids in Folium Isatidis,R284
  5. Determination of Toxic Nitrogen Compounds by Capillary Electrophoresis,O658.9
  6. The Study of the New Type Cycoldextrin Derivatives Applied in CE,O658.9
  7. High-through Detection Method Application in Maize SSR Genetic Linkage Map Construction,S513
  8. Study on Digitized Fingerprints of Mylabris and Compound Capsules Cantharidin,R284
  9. Study on the Enantiomer Separation of Three Chiral Pesticides and Its Stereoselective Environmental Behavior,TQ450.2
  10. Applications of Capillary Electrophoresis in Natural Products and Environment,O658.9
  11. The Study of Solid Electrochemiluminescence Sensor Based on Carbon Nanofiber,TP212.2
  12. Lipase Immobilized on Magnetic Muti-Walled-Carbon Nanotubes Catalyzed Resolution of α-Phenylethanol,R914
  13. Study on the Sensitive Determination of Macrolides by Capillary Electrophoresis with Electrochemiluminescence Detection and Applications,R927
  14. Preparation and Application of Capillaries Modified by Polymers with Different Charge,O657.8
  15. Stereoisomer Analysis of β-adrenergic Receptor Blockers in Wasterwater Samples,R123.1
  16. The hydrochloric acid mabuterol synthesis process,TQ463
  17. Studies of Analytical Method and Pharmacokinetics of Pantoprazole in Rats,R96
  18. Enantiomeric Separation of Selected Pharmaceuticals on Chiral Stationary Phases by HPLC and Study on Pharmacokinetics,R96
  19. Trace fluoroquinolones line preconcentration method of capillary electrophoresis,R155.5
  20. Capillary electrophoresis analysis of food and fluids fluoroquinolone residues,R155.5
  21. Experimental system based on TMS320F2812 Design and Application,TP368.12

CLC: > Medicine, health > Pharmacy > Pharmacology
© 2012 www.DissertationTopic.Net  Mobile