Preclinical pharmacokinetic studies of 3'-azido-2',3'-dideoxyuridine and its novel prodrugs

Abstract

3'-Azido-2',3'-dideoxyuridine (AZDU, AzddU, CS-87, Uravidine) is a nucleoside analog with a similar chemical structure to 3'-azido-3'-deoxythymidine (AZT, zidovudine), the most frequently used drug in the treatment of HIV-infected patients. AZDU has been found to have potent anti-HIV activity in human peripheral blood mononuclear cells with significantly reduced human bone marrow toxicity, 30-fold less than AZT. Nevertheless, the potential of AZDU as a promising anti-HIV agent has been limited by its relatively short half-life, relatively low bioavailabilities as illustrated in various animal models as well as its extensive glucuronidation in HIV-infected patients. | As means of improving its pharmacokinetic profile, several novel compounds were synthesized as prodrugs of AZDU in order to obtain prolonged half-lives and good bioavailabilities. | Oral bioavailabilities of AZDU were determined in rats. A rapid, sensitive, reproducible high performance liquid chromatography (HPLC) method using gradient elution was developed to simultaneously quantitate AZDU and its prodrugs in rat plasma. Preclinical pharmacokinetic studies on one of the prodrugs, 3'-azido-2',3'- dideoxyuridine-5'-O-valinate hydrochloride, showed improved bioavailability of AZDU compared with that obtained after oral administration of the parent drug. Therefore, AZDU-VAL is a promising prodrug of AZDU. | 2'-Amino-6-cyclopropylamino-9-(2',3'-dideoxy-?-D-glycero-pent-2- enofuranosyl) purine (DV) was recently synthesized as a prodrug of the anti-HIV nucleoside analog 2', 3'-dideoxydidehydroguanine (D4G). In the present dissertation, a reliable, sensitive isocratic HPLC analytical method was developed to determine ADV in rat plasma and rat liver homogenates. This analytical method was employed in the bioconversion studies of ADV in vitro.