5′-Aminocarbonyl Phosphonates as New Zidovudine Depot Forms: Antiviral Properties, Intracellular Transformations, and Pharmacokinetic Parameters
| Autor: | Vsevolod A Khalizev, Alexander V. Shipitsin, Elena A. Shirokova, Anastasia L. Khandazhinskaya, Marina K. Kukhanova, Stanislav I Shram, Maxim V. Jasko, Dmitry V. Yanvarev, Yuriy S Skoblov |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy viruses Biological Availability Pharmaceutical Science Pharmacology Cell Line Zidovudine Dogs Pharmacokinetics immune system diseases Oral administration medicine Animals heterocyclic compounds Biotransformation biology Reverse-transcriptase inhibitor virus diseases biochemical phenomena metabolism and nutrition Virology Bioavailability Enzyme inhibitor Delayed-Action Preparations Toxicity biology.protein Reverse Transcriptase Inhibitors Female Rabbits Nucleoside medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 37:494-501 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.108.022269 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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