azidothymidine

azidothymidine
IUPAC name	3'-azido-3'-deoxythymidine
CAS number	30516-87-1
DrugBank	DB00495
PubChem	35370
ChemSpiderID	32555
Molecular weight	267.24 g/mol

azidothymidine. Also known by its generic name zidovudine and the abbreviation AZT, it is a nucleoside analog reverse-transcriptase inhibitor. It was the first antiretroviral medication approved for the treatment of HIV/AIDS and became a cornerstone of early therapy. Its development marked a pivotal moment in the fight against the AIDS pandemic, transforming a fatal diagnosis into a manageable chronic condition.

History and development

The compound was first synthesized in 1964 by Jerome P. Horwitz at the Michigan Cancer Foundation, initially investigated as a potential anti-cancer agent. Following the identification of HIV as the causative agent of AIDS in the early 1980s, researchers at the National Cancer Institute, including Samuel Broder and Hiroaki Mitsuya, began screening compounds for antiviral activity. In 1985, azidothymidine was identified as a potent inhibitor of HIV replication in laboratory studies. A pivotal clinical trial conducted by the Burroughs Wellcome company demonstrated significant survival benefits, leading to its accelerated approval by the U.S. Food and Drug Administration in 1987, a landmark event in pharmaceutical history. The drug's rapid development was heavily influenced by advocacy from groups like ACT UP.

Medical uses

Azidothymidine is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents as part of highly active antiretroviral therapy. It is also a key component in the prevention of mother-to-child transmission of HIV during pregnancy, labor, and delivery. Furthermore, it is used for post-exposure prophylaxis following occupational exposures, such as needlestick injuries, in healthcare settings. Its use is guided by treatment guidelines established by organizations like the World Health Organization and the U.S. Department of Health and Human Services.

Mechanism of action

As a nucleoside analog, azidothymidine is a prodrug that requires intracellular phosphorylation by host cell kinases to its active triphosphate form. This active metabolite, AZT-triphosphate, competitively inhibits the viral enzyme reverse transcriptase and acts as a chain terminator during DNA synthesis. By incorporating itself into the growing viral DNA chain, it prevents further elongation, thereby halting the replication of the HIV genome. This mechanism is specific to retroviruses like HIV and does not significantly affect human DNA polymerase under therapeutic conditions.

Adverse effects and resistance

Early high-dose therapy was associated with significant toxicities, including severe anemia and neutropenia due to bone marrow suppression. Other common adverse effects include myopathy, lactic acidosis, and hepatic steatosis. Long-term use can lead to lipodystrophy and insulin resistance. The emergence of drug-resistant strains of HIV, particularly those with mutations in the reverse transcriptase gene such as M184V, can compromise clinical efficacy. Resistance monitoring is a standard part of management in clinics like the Johns Hopkins Hospital.

Pharmacokinetics

Azidothymidine is well absorbed following oral administration, but it undergoes significant first-pass metabolism, resulting in a bioavailability of approximately 60-70%. It is primarily metabolized in the liver by glucuronidation via the enzyme UGT2B7 to an inactive glucuronide metabolite. The drug and its metabolite are eliminated renally. It readily crosses the blood-brain barrier and the placenta, which is critical for its role in preventing central nervous system infection and perinatal transmission. Its pharmacokinetics can be altered by concomitant use of medications like probenecid or valproic acid.

Society and culture

The approval and pricing of azidothymidine were subjects of intense controversy and public debate, involving protests by ACT UP at the FDA headquarters and Burroughs Wellcome. Its development is chronicled in works like Randy Shilts's book And the Band Played On. The drug's impact is also depicted in films such as Dallas Buyers Club. The high initial cost sparked discussions about drug pricing and access to medicines in the developing world, influencing programs like the President's Emergency Plan for AIDS Relief. It is listed on the World Health Organization Model List of Essential Medicines.

Category:Antiviral drugs Category:HIV/AIDS