Drug Metab Dispos, 2009, 37(3):494-501

5′-aminocarbonyl phosphonates as new zidovudine depot forms: Antiviral properties, intracellular transformations, and pharmacokinetic parameters

The main disadvantages of 3′-azido-3′-deoxythymidine (zidovudine, AZT), the most common anti-HIV drug, are toxicity and a short half-life 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 t1/2and Tmaxvalues 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 Cmaxand Cmin. Such a combination of properties makes the compounds of this group promising for further studies as extended-release forms of AZT. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.

Khandazhinskaya AL, Yanvarev DV, Jasko MV, Shipitsin AV, Khalizev VA, Shram SI, Skoblov YS, Shirokova EA, Kukhanova MK

IBCH: 478
Ссылка на статью в журнале: http://dmd.aspetjournals.org/cgi/doi/10.1124/dmd.108.022269
Кол-во цитирований на 10.2023: 20
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