Development History and General Characteristics
The drug was synthesized in 1964 as an anticancer agent, but it showed no efficacy in that role. Years later, the situation changed, and in 1987 the medication was approved as the first specific agent to combat HIV infection.
Chemically, the compound is a synthetic analogue of the nucleoside thymidine. Its key structural feature is the replacement of the 3'-hydroxyl group in the deoxyribose molecule with an 3'-azido group.
Metabolism and Mechanism of Antiviral Action
Upon entering the body, zidovudine undergoes three-step phosphorylation to its active metabolite, zidovudine triphosphate. Because the human immunodeficiency virus lacks its own kinases, this process is carried out exclusively by host cell enzymes.
During replication, the active metabolite competes with natural deoxythymidine for incorporation into the growing viral DNA chain. Once incorporated, DNA synthesis stops because the lack of a 3'-hydroxyl group prevents the attachment of the next nucleotide. The primary target for the drug is HIV reverse transcriptase.
Selectivity and Spectrum of Activity
The drug demonstrates selectivity by inhibiting viral reverse transcriptase much more strongly than human DNA polymerases. However, the mitochondrial isoform of the enzyme in the human body can become a target for adverse effects.
- Spectrum of activity: infections caused by HIV-1 and HIV-2.
- Clinical scenarios: early stages of the disease, as well as prevention of vertical transmission from mother to fetus (transplacental route).
- Formulations: tablets, capsules, oral solutions, and parenteral injection solutions.
Pharmacokinetics and Elimination
Zidovudine is well absorbed from the gastrointestinal tract, but its bioavailability is about 65% due to the first-pass hepatic effect.
- Distribution: the active substance penetrates into almost all tissues and biological fluids, crossing the placenta and the blood-brain barrier (BBB).
- Elimination: excretion occurs via the kidneys in unchanged form and as glucuronide metabolites.
Safety Profile and Toxicity
Due to its activation pathway, zidovudine accumulates not only in infected cells but also in healthy cells, leading to adverse effects:
- Hematotoxicity: suppression of replication in rapidly dividing tissues increases the risk of anemia and neutropenia.
- Mitochondrial toxicity: impaired DNA synthesis in mitochondria can cause myopathy.
- Hepatotoxicity: hepatic steatosis and lactic acidosis may occur.
- Neurotoxic and general reactions: headache, insomnia, dyspepsia, fever, and skin rash, which are often transient.