Zidovudine

Absorption

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.

Toxicity

Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD50 is 3084 mg/kg (orally in mice).

Description

Zidovudine, also known as azidothymidine (AZT), is an antiviral agent acting via reverse transcnptase inhibition. It was first launched in the U.K. and subsequently introduced in over a dozen countries for the management of severe manifestations of HIV infection. In patients with AIDS and ARC, zidovudine reduces the risk of opportunistic infections and prolongs survival time. In symptom-free patients it shows promise in halting further immunological deterioration.

The Uses of Zidovudine

Zidovudine is an antiretroviral drug that is clinically active against HIV-1 and is intended to treat HIV-infected patients. Zidovudine is an analog of thymidine that inhibits replication of the AIDS virus. It also turned into mono-, di-, and triphosphates by the same cellular enzymes that catalyze phosphorylation of thymidine and thymidine nucleosides. Zidovudine-triphosphate is then included in the terminal fragment of the growing chain of viral DNA by viral reverse transcriptase, thus causing the viral DNA chain to break apart in cells infected with the virus.
Zidovudine has been authorized for treating patients with AIDS. It significantly prolongs the life of the patient, although it has a number of toxic effects. Synonyms of this drug are azidothymidine and retrovir.

Indications

Used in combination with other antiretroviral agents for the treatment of human immunovirus (HIV) infections.

Background

A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [PubChem]

What are the applications of Application

3′-Azido-3′-deoxythymidine is an inhibitor of HIV-1 reverse transcriptase

Pharmacokinetics

Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

Metabolism

Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT).