Zidovudine (AZT) is a deoxythymidine analog that requires anabolic phosphorylation for activation to the 5′-triphosphate form. After entering the cell by passive diffusion, zidovudine is phosphorylated via three cellular kinases; the triphosphate is a competitive inhibitor of deoxythymidine triphosphate for the reverse transcriptase. Additionally, it acts as a chain terminator in the synthesis of proviral DNA. Zidovudine has in vitro activity against HIV-1, HIV-2, and the human T cell lymphotropic viruses.
Resistance: Zidovudine resistance is due to mutations in the reverse transcriptase gene and is more frequent in persons with advanced HIV infection. Withdrawal of zidovudine exposure may permit the reversion of HIV-1 isolates to the susceptible (wild-type) phenotype.
Pharmacokinetics: Zidovudine is available in intravenous and oral formulations. It is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are approximately 60% of those in serum. Substantial first-pass metabolism to an inactive glucuronidated metabolite results in a systemic bioavailability of approximately 65%.
Clinical Uses: Zidovudine inhibits replication of HIV-1 in infected individuals and has been shown to decrease the rate of clinical disease progression and prolong survival. Zidovudine has efficacy in the treatment of HIV-associated encephalopathy and thrombocytopenia, and in the prevention of vertical (mother to newborn) transmission of HIV. Clinical efficacy is limited by the relatively rapid development of resistance, particularly when used as monotherapy.
Adverse Reactions: The most common adverse effect is myelosuppression gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve if ingestion is continued. Less frequent unwanted effects include thrombocytopenia, acute cholestatic hepatitis, and myopathy.
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