Zidovudine (azidothymidine, AZT) is a thymidine analogue. Within the virus-infected cell, the 3′-azido group is used by retroviral reverse transcriptase and incorporated into DNA transcription, preventing viral replication. The shared mechanism of action is inhibition of RNA-dependent DNA polymerase (reverse transcriptase). This enzyme is responsible for conversion of the viral RNA genome into double-stranded DNA before it is integrated into the cell genome. Because these actions occur early in replication, the drugs tend to be effective for acute infections but are relatively ineffective for chronically infected cells. Cellular α-DNA polymerases are inhibited only at concentrations 100-fold greater than those necessary to inhibit reverse transcriptase, thus rendering this drug relatively safe to host cells. Cellular γ-DNA polymerase, however, is inhibited at lower concentrations.
AZT is effective against a variety of retroviruses at low concentrations. Resistance to AZT is associated with point mutations resulting in amino acid substitutions in the reverse transcriptase. Prolonged use of AZT can facilitate viral resistance. The risk of resistance also appears to correlate with CD4 cell count and the state of infection. Viral susceptibility to AZT may return after the drug has been discontinued for a period of time.
Granulocytopenia and anemia are the major adverse effects of AZT in human patients. The risk of toxicity increases in human patients with low (CD4) lymphocyte counts, high doses, and prolonged therapy. Granulocyte colony-stimulating factor is indicated for management of granulocytopenia. CNS adverse effects are more likely as therapy is begun. The risk of myelosuppression is increased by drugs that inhibit glucuronidation or renal excretion and may be increased in cats.
After a single dose of AZT at 25 mg/kg in cats, bioavailability is ~75%–100%. The elimination half-life is ~1.5 hr, and volume of distribution is 0.82 L/kg. Drug concentrations remain above the effective concentration 50 (EC50) of 0.19 mcg/mL for feline immunodeficiency virus for at least 24 hr after either IV or PO administration. Although this concentration is higher than that associated with myeloid suppression of human cells, adverse effects in cats are limited to transient restlessness, mild anxiety, and hemolysis.
Studies in cats regarding the efficacy of AZT (10–20 mg/kg, bid for 42 days) for feline leukemia virus infection indicated that AZT prevents retroviral infection if administered immediately after viral exposure and may reduce replication if administered to previously infected animals. Serum-neutralizing antibodies developed in some of the infected cats, and the cats became resistant to subsequent viral challenge. There was no altered progression of disease in cats when treatment was withheld until 28 days after infection, although the level of viremia was much lower than in untreated cats. AZT appeared to be nontoxic in uninfected cats, although 3 of 12 infected kittens became anorectic and icteric and were vomiting after 40 days of treatment. AZT may cause Heinz body anemia. CBCs should be performed on cats receiving AZT.