The Studies On Pharmacokinetics And Tissue Distribution Of PMEA Prodrugs

ADV, is a produrg of PMEA(adeofvir), the activity in vitro and vivo of ADV shows antiviral activity. In the hepatitisB virus setting,ADV inhibits both the wild type and lamivuding-resistant HBV strains. It was widely used to anti-virus in clinic including HBV. In the clinical studies of longer term, the oral prodrug of adefovir(PMEA), ADV shows dose-limiting renal toxicity, the 30 mg/d dosage was associated with a significantly higher incidence of serum creatinine increases than the 10 mg/d dosage. Toxic effects and severity of the drug concentration and time and a positive correlation, has severely limited the clinical application. The purpose of this issue is studying early pharmacokinetics and tissue distribution of the adefovir prodrugs.We selected ADV analogues M1, M2 through the Beagle dogs and SD rats. Use ADV for the reference standard drug, compared the bioavailability of M1, M2.Because ADV, M1, M2 rapid metabolize to the active substances - PMEA in vivo, we determined testing PMEA to reflect the concentration of M1 and M2 in blood and tissue distribution change.This thesis established method separately by HPLC/MS Determination of PMEA in beagle dogs and concentration of SD rat tissues, and validated the method systematically. Through animal experiments and compared the prodrugs of adefovir, M1 and M2,which synthesized by Beijing shiqiao Biological Pharmaceutical Co., Ltd. and provide a theoretical foundation for further exploitation.Part I: established the HPLC/MS method to determine PMEA in the plasma of beagle dogs, as PMEA for the determination drug, ganciclovir for the internal standard, verified the method of HPLC/MS systematically. studied the pharmacokinetics of the ADV, M1 and M2 in dogs, compared the relative bioavailability of three prodrugs. Pharmacokinetic study showed that: after gavage administration, the average drug concentration in plasma: ADV> M1> M2. The comparison on the resultes of relative bioavailability: AUCM1/AUCADV=52.81%, AUCM2/AUCADV=38.90%.Part II: established the HPLC/MS method to determine PMEA in rat tissues researched distribution of ADV, M1 and M2 in liver, kidney and intestine of SD rats. Tissue distribution study shows that: in the liver: M2>M1>ADV. in the kidney: ADV>M1>M2, in the intestine: ADV>M2>M1, showed that M2 improved the PMEA distribution in the liver, it has more targeting to the liver than M1 and ADV and lower nephrotoxicity.