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The Studies on Pharmacokinetics and Tissue Distribution of PMEA Prodrugs

Author: ZhongLing
Tutor: ShangJingChuan
School: Chongqing Medical University
Course: Medicinal Chemistry
Keywords: PMEA HPLC / MS Pharmacokinetics The relative bioavailability of
CLC: R96
Type: Master's thesis
Year: 2009
Downloads: 139
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Abstract


Adefovir dipivoxil (adefovir dipivoxil, ADV) Adefovir (adefovir, PMEA) Special valerate , broad-spectrum antiviral activity in vitro and in vivo have been clinically widely used for chronic hepatitis B treatment. However , animal and human studies show that oral ADV has a significant concentration dependent renal toxicity , and toxic effects and severity of concentration and treatment time was positively correlated , severely limits the clinical application . The purpose of the experimental study of the early pharmacokinetics and tissue distribution of newly synthesized adefovir precursor drugs M1 and M2 . Choice the Beagle dogs WISTER rats screening ADV analogues M1, M2, as a reference drug , M1 and M2 and ADV relative bioavailability to ADV . ADV, M1, M2 rapidly metabolized in the body as the active substance PMEA, test mainly through the determination of the concentration of PMEA , to reflect changes in the concentration of the serum concentration and tissue distribution of M1 and M2 in animals . Of this thesis were to establish a high-performance liquid chromatography-mass spectrometry (HPLC / MS) method for the determination of PMEA in the distribution the beagle dog plasma WISTER of rat tissues and systems methodology confirmation . Filtering through animal experiments and ADV synthetic ester prodrug of adefovir Biological Pharmaceutical Co., Ltd. and Beijing World Bridge M1 and M2 provide some theoretical basis for the further development of new drugs for the anti-liver . The first part : the establishment of PMEA in Dog Plasma by HPLC / MS determination method . ADV with M1, M2 in beagle dogs pharmacokinetic dynamics , comparing the relative bioavailability of three . PMEA for the determination of drug ganciclovir as an internal standard , the establishment of the HPLC / MS method for measuring , and method validation of the system . Pharmacokinetic studies showed that : The mean plasma drug concentrations after gavage administration ADV gt; M1 gt ; M2 , the relative biological utilization comparison results of the latter two relative bioavailability : AUC value standard of ADV calculated F were 52.81% and 38.90% , respectively . Part II: Building PMEA HPLC / MS Method for determination in rat tissues . Research ADV and M1, M2 in WISTER rat tissue distribution of the liver, kidney, intestines . Tissue distribution studies show that : liver M2 gt; M1 gt; ADV . The renal drug content ADV gt; M2 gt ; the M1 , intestinal the drug content ADV gt ; M2 gt ; M1 the improve PMEA distribution in the liver , that prodrugs M2 M1, ADV more liver targeting and lower renal toxicity.

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