| Chronic hepatitis B virus (HBV) infection remains a major worldwide public health problem. It is one of the principal causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma, is associated with high morbidity and mortality and remains a significant healthcare issue. The clinical drugs often used, such as interferon-a and Iamivudine (3-TC), provide therapeutic options for the treatment of chronic hepatitis B. However, both agents have a low cure rate and drug resistance develope, respectively. ADV, a prodrug of PMEA (9-[2-(phosphonomethoxy) ethyl] adenine; adefovir), is an acyclic nucleotide analog with potent and selective inhibitory activity against retrovirus replication. The in vitro and in vivo activity of ADV shows a broad spectrum of antiviral activity. In the hepatitis B 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 has been reported to produce renal tubular damage, characterized by mild to moderate elevation of serum creatinine, electrolyte abnormalities, proteinuria and glycosuria, particularly when the drug is used for prolonged therapy and higher doses for HBV therapy.A series of novel ADV analogues prodrugs were synthized with the aim of increasing the chemical and enzymatic stability of their ester-bond moiety. The purpose of t he p resent s tudy w as t o c ompare t he p harmacokinetics o f t hese a nalogues a nd t o explore their metabolic fates in vitro. In order to evaluate the pharmacokinetics of ADV and its analogues, the rat plasm and liver S-9 incubating system were used. This article is divided into two parts:In the first part, a rapid, simple and accurate ion-pair-RP-HPLC-UV method was established to determine the ADV, its analogues and metabolites in rat plasm and liver S-9 in vitro. The developed analytical method has a relatively good sensitivity, selectivity and reproductivity, and it can provide important reference method to adapt for the preclinical and clinical pharmacokinetics studies.Three analogues of ADV were evaluated for their stability in rat plasm and liver S-9 in vitro. The analogue II showed to be more stable in rat plasm than the other two, which could be transformed into active structure in the plasm and liver S-9 through a relative simple metabolic pathway, that is, prodrug-intermediate-PMEA. Analogue II seems to be a better hit structure and was recommended for further development.In the second part, seven derivates of Analogue II were evaluated in rat plasm and liver S-9 in vitro. The obtained results showed that there were faster rates of producing/eliminating, and higher amounts of PMEA in liver S-9 than in rat plasm. It suggests the seven derivates of analogue II were more stable in plasm than in liver S-9, and can be degraded specificIy in liver S-9. Furthermore, Derivate II -1, Derivate II -2, DerivateII-3, Derivate II-4, Derivate II-5 and Derivate II-6 were more stable than Derivate II in plasm. To take stability in plasm into consideration, the six new Derivates showed the metabolic properties as we designed.Compared with metabolic properties of ADV, series of Analogs II showed different metabolic properties in both models, which could produce more motabilites or none, respectively. These properties might cause undesirable potential toxicity issues or pharmacological effects to different human. |
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