VOL.: 76 (2000) (p. 73)
CAS No.:
Chem. Abstr. Name: 3¢-Azido-3¢-deoxythymidine
Zidovudine (AZT) is a nucleoside analogue that has been used in the treatment and prevention of HIV infection in adults and children since the mid-1980s. Zidovudine is in widespread use in combination regimens with other antiretroviral agents. It is currently indicated in the treatment of HIV-positive pregnant women and to prevent mother-to-infant transmission.
5.2 Human carcinogenicity data
No difference in the incidence of non-Hodgkin lymphoma relative to that in the general population was seen before and after introduction of zidovudine therapy.
In a large case–control study from the USA of HIV-infected patients, no association was found between the incidence of non-Hodgkin lymphoma and therapeutic use of zidovudine.
A large cohort study from the USA with limited length of follow-up suggested a linear increase in the cumulative risk for non-Hodgkin lymphoma over time among adult patients with AIDS, but this was not related to treatment with zidovudine. A number of other cohort studies were available which also involved limited length of follow-up and few subjects. No data were available on the risks for types of cancers other than non-Hodgkin lymphoma.
None of the studies provided information on the risk for cancer associated with use of zidovudine for more than three years.
5.3 Animal carcinogenicity data
Zidovudine was tested for carcinogenicity in mice and rats by oral administration, in mice by intravaginal administration and in mice by transplacental and by transplacental and postnatal exposure. Zidovudine was also administered with 12-O-tetradecanoylphorbol 13-acetate (TPA) in a transplacental experiment in mice and in combination with a-interferon in mice.
Administration of zidovudine by gavage induced vaginal squamous-cell carcinomas in two studies in mice. A low incidence of vaginal tumours was observed in rats treated with the highest dose. Administration of zidovudine to mice by the intravaginal route resulted in an increased incidence of vaginal squamous-cell carcinomas. Combined administration of zidovudine with a-interferon also induced vaginal tumours in mice. Vaginal squamous-cell tumours are very rare in untreated animals.
Transplacental administration to mice resulted in an increased incidence and multiplicity of lung and liver tumours and in an increased incidence of female reproductive tract tumours in one study, whereas no increased tumour incidence was associated with treatment in another study at a lower dose. After transplacental and postnatal administration of zidovudine to mice, an increased incidence of vaginal squamous-cell carcinomas was seen. Zidovudine given transplacentally followed by postnatal topical application of TPA to mice resulted in an increased incidence and multiplicity of skin tumours (mostly papillomas).
5.4 Other relevant data
The pharmacokinetics of zidovudine in humans shows large inter- and intra-individual variation. The achievement of maximum plasma concentrations and removal from plasma of the parent compound are rapid except in patients with compromised renal function. The pharmacokinetics in nonhuman primates is virtually identical to that in humans. The absorption, distribution and elimination of zidovudine in rodents are more rapid than in humans, and its bioavailability is higher in rats and mice than in primates. Zidovudine is metabolized by three pathways: glucuronidation, which accounts for up to three-quarters of the human urinary product; mixed-function oxidase-mediated reactions, giving 3¢-amino-3¢-deoxythymidine, a minor urinary metabolite; and phosphorylation, which is fundamental to the antiviral activity of zidovudine but accounts for only about 1% of its total disposition. Unchanged zidovudine constitutes up to one-fifth of the human urinary products. In rats and mice, unchanged drug accounts for up to 90% of the urinary recovery, which represents about 80% of the dose; the remaining urinary products consist of five metabolites, which have been identified.
The serious adverse effects of treatment with zidovudine, reported in a small proportion of people, include haematotoxicity (anaemia, neutropenia), hepatotoxicity and cardiac and skeletal myopathy (due to mitochondrial effects). Similar toxic effects are found in treated mice.
Zidovudine crosses the placenta by bidirectional passive diffusion, and the drug and its monophosphate and monoglucuronide metabolites were observed in fetal tissue. Studies of children up to 4.2 years of age who had been exposed in utero and for up to six weeks after birth to zidovudine provided no evidence for an increased incidence of structural developmental abnormalities or cognitive or immune dysfunction. Studies in mice, rats and rabbits given zidovudine transplacentally showed no increase in the frequency of malformations, but some studies showed increased numbers of fetal resorptions and decreased fetal weights after oral administration of zidovudine at doses of 200–500 mg/kg bw per day during gestation. Studies in monkeys and rats indicated that the behavioural alterations in offspring exposed to zidovudine in utero were generally reversible.
Zidovudine is incorporated into nuclear and mitochondrial DNA in mammalian cells in culture, in experimental animals and in humans. It appears to cause mutations primarily by inducing large deletions, consistent with its action as a DNA chain terminator. It produces clastogenic effects in cultured human cells and in mice exposed to either high or clinically relevant concentrations. Analyses of mutations induced in human cells in culture and in skin tumours from transplacentally treated mice showed that exposure to zidovudine also causes point mutations.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of zidovudine.
There is sufficient evidence in experimental animals for the carcinogenicity of zidovudine.
Overall evaluation
Zidovudine is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Synonyms
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Toxicological Abbreviations