5'-Aminocarbonyl Phosphonates as New Zidovudine Depot Forms: Antiviral Properties, Intracellular Transformations, and Pharmacokinetic Parameters (original) (raw)
2009, Drug Metabolism and Disposition
The main disadvantages of 3-azido-3-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short halflife in the organism. The introduction of an H-phosphonate group into the AZT 5 position resulted in significant improvement of its therapeutic properties and allowed a new anti-HIV drug, Nikavir (AZT H-phosphonate). In this work, we described a new group of AZT derivatives, namely, AZT 5-aminocarbonylphosphonates. The synthesized compounds displayed antiviral properties in cell cultures infected with HIV-1 and the capacity to release the active nucleoside in animals (rabbits and dogs) in a dose-dependent manner. The compounds were less toxic in MT-4 and HL-60 cell cultures and experimental animals compared with AZT. Major metabolites found in MT-4 cells after their incubation with AZT 5-aminocarbonylphosphonate 1 were AZT and AZT 5-phosphate (25 and 55%, respectively). Among the tested compounds, phosphonate 1 was the most effective AZT donor, and its longest t 1/2 and T max values in the line phosphonate 1 -AZT H-phosphonate -AZT imply that compound 1 is an extended depot form of AZT. Although bioavailability of AZT after oral administration of phosphonate 1 was lower than those of AZT H-phosphonate and AZT (8 against 14 and 49%), we expect that this reduction would not cause essential decrease of antiviral activity but noticeably decrease toxicity as a result of gradual accumulation of AZT in blood and the absence of sharp difference between C max and C min . Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT.
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