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.

Chemical properties

Off White Crystalline Powder

Originator

Detroit Inst. Cancer Res. (USA)

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.

The Uses of Zidovudine

A potent and selective inhibitor of HIV-1 replication

The Uses of Zidovudine

antibacterial

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A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group.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

Definition

ChEBI: A pyrimidine 2',3'-dideoxyribonucleoside compound having a 3'-azido substituent and thymine as the nucleobase.

Indications

Zidovudine was the first agent to be used to prevent the transmission of HIV from a pregnant woman to her child. It was given to the mother at 14 to 34 weeks’ gestation and to the child for the first 6 weeks of life. Current combination therapies employ zidovudine with another NRTI and a protease inhibitor.

Manufacturing Process

Preparation of 2,3'-anhydrothymidine
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 mL dry DMF (dimethyl formamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)diethylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963)]. This solution was heated at 70°C for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'- anhydrothymidine; melting point 228°-230°C.
Preparation for 3'-azido-3'-deoxythymidine
2,3'-Anhydrothymidine (25 g; 0.1115 mol) and NaN 3 (29 g; 0.446 mol) was suspended in a mixture of 250 mL DMF and 38 mL H 2 O. The reaction was refluxed for 5 hours at which time it was poured into 1 liter of H 2 O. This aqueous solution was extracted with ethyl acetate (EtOAc) (3x700 ml). The EtOAc was dried over Na 2 SO 4 , filtered, and then EtOAc was removed in vacuo to yield a viscous oil. This oil was stirred with 200 mL water resulting in a solid, 3'-azido-3'-deoxythymidine, 9.15 g (0.0342 mol); 30.7%; melting point 116°-118°C.

brand name

Retrovir (GlaxoSmithKline).

Therapeutic Function

Antiviral, Antineoplastic

Antimicrobial activity

Zidovudine is active against HIV-1, HIV-2 and HTLV-1.

Acquired resistance

As with stavudine, mutations at position 41, 67 and 70, and positions 210, 215 and 219 (the ‘thymidine analog mutations’) of the reverse transcriptase genes are associated with diminished antiretroviral efficacy.

General Description

Slightly off-white odorless powdery solid.

General Description

Zidovudine, 3'-azido-3'-deoxythymidine or AZT, is ananalog of thymidine that possesses antiviral activityagainst HIV-1, HIV-2, HTLV-1, and several other retroviruses.This nucleoside was synthesized in 1978 by Linand Prusoff as an intermediate in the preparation ofamino acid analogs of thymidine. A screening program directedtoward the identification of agents potentially effectivefor the treatment of patients with AIDS led to the discoveryof its unique antiviral properties 7 years later.
Zidovudine is recommended for the management of adultpatients with symptomatic HIV infection (AIDS or ARC)who have a history of confirmed Pneumocystis carinii pneumoniaor an absolute CD4⁺(T4 or T_H cell) lymphocytecount below 200/mm³ before therapy. The hematologicaltoxicity of the drug precludes its use in asymptomatic patients.Anemia and granulocytopenia are the most commontoxic effects associated with AZT.

General Description

Zidovudine, or 3u-azido-3udeoxythymidine, formerly known as azidothymidine (AZT; BW A509U), is an analog of the nucleoside thymidine. It is an inhibitor of the human immunodeficiency virus (HIV)-encoded enzyme reverse transcriptase. It was the first antiretroviral compound to be licenced for the treatment of people infected with HIV. The compound was synthesized much earlier, however, by Horwitz and colleagues and subsequently used in anticancer research. Zidovudine was developed by Burroughs Wellcome and is now marketed by GlaxoSmithKline under the trade name of Retrovir. Zidovudine is also available in fixed-dose cominations with other nucleoside analog reverse transcriptase inhibitors as Combivir (zidovudine with lamivudine) and Trizivir (zidovudine with lamivudine and abacavir). Generic forms of the drug have been produced by a number of companies and include AVIRO-Z (Ranbaxy Laboratories Ltd) and Zidovir (Cipla Ltd). There are also a number of generic fixed-dose products including zidovudine with lamivudine (e.g. Duovir; Cipla Ltd). Zidovudine is indicated for the treatment and prevention of HIV infection, generally given in combination with other antiretroviral agents.

Air & Water Reactions

Dust may form an explosive mixture in air. Water soluble. Hydrolysis occurs in strongly basic solutions .

Reactivity Profile

Zidovudine is a azido compound. Azo, diazo, azido compounds can detonate. This applies in particular to organic azides that have been sensitized by the addition of metal salts or strong acids. Toxic gases are formed by mixing materials of this class with acids, aldehydes, amides, carbamates, cyanides, inorganic fluorides, halogenated organics, isocyanates, ketones, metals, nitrides, peroxides, phenols, epoxides, acyl halides, and strong oxidizing or reducing agents. Flammable gases are formed by mixing materials in this group with alkali metals. Explosive combination can occur with strong oxidizing agents, metal salts, peroxides, and sulfides.

Fire Hazard

Flash point data for Zidovudine are not available; however, Zidovudine is probably combustible.

Pharmaceutical Applications

An analog of thymidine formulated for oral or intravenous use.

Biochem/physiol Actions

Reverse transcriptase inhibitor active against HIV-1 virus.

Mechanism of action

Zidovudine (AZT , ZDV) is an analogue of thymidine in which the azido group is substituted at the 3-carbon atom of the dideoxyribose moiety. It is active against RNA tumor viruses (retroviruses) that are the causative agents of AIDS and T-cell leukemia. Retroviruses, by virtue of RT, direct the synthesis of a provirus (DNA copy of a viral RNA genome). Proviral DNA integrates into the normal cell DNA, leading to the HIV infection. Zidovudine is converted to 5′-mono-, di-, and triphosphates by the cellular thymidine kinase. These phosphates are then incorporated into proviral DNA, because RT uses ZDV-triphosphate as a substrate. This process prevents normal 5′,3′-phosphodiester bonding, resulting in termination of DNA chain elongation because of the presence of an azido group in ZDV. The multiplication of HIV is halted by selective inhibition of RT and, thus, viral DNA polymerase by ZDV-triphosphate at the required dose concentration. Zidovudine is a potent inhibitor of HIV-1, but it also inhibits HIV-2 and EBV.

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.

Pharmacokinetics

Oral absorption: 65%
C_max 300 mg twice daily: 2.3 mg/L
Plasma half-life: 1.1 h
Volume of distribution: 1.6 L/kg
Plasma protein binding; 34–38%
Absorption and distribution
It is absorbed rapidly and almost completely following oral administration. Absorption is not significantly affected by food. It appears to undergo widespread body distribution. CNS penetration is fairly good. The semen:plasma ratio varies from 0.95 to 13.5 (mean 5.9). It is secreted into breast milk.
Metabolism and excretion
Following hepatic metabolism (glucuronidation), elimination is primarily renal. After oral administration, urinary recovery of zidovudine and its glucuronide metabolite accounted for 14% and 74% respectively of the dose, with a total urinary recovery of 90%.
In severe renal impairment, clearance was about half that reported in subjects with normal renal function Accumulation may occur in patients with hepatic impairment due to decreased glucuronidation.

Clinical Use

Treatment of HIV infection in adults and children (in combination with other antiretroviral drugs)
Reduction of maternal transmission of HIV to the fetus

Side Effects

In common with other drugs in this class, use has been associated with episodes of fatal and non-fatal lactic acidosis and hepatomegaly with steatosis. Careful clinical evaluation is needed in patients with evidence of hepatic abnormality. Myelosuppression may occur within the first 4–6 weeks of therapy. Hematological parameters should be monitored during this period, with prompt dose modification or switch if abnormalities are observed. Treatment with reduced doses may be attempted in some patients once bone marrow recovery has been observed. Myopathy is rarely seen with the use of the current dosing regimens.
Co-administration with drugs known to cause nephrotoxicity, cytotoxicity or which interfere with red or white blood cell number and function may increase the risk of toxicity. Probenecid and trimethoprim may reduce renal clearance of zidovudine, and other drugs that are metabolized by glucuronidation may interfere with its metabolism.

Safety Profile

Moderately toxic by intravenousroute. Human systemic effects by ingestion: aplasticanemia, changes in blood cell count, convulsions or effect on seizure threshold, headache, nails, retinal changes.Human mutation data reported.

Synthesis

Zidovudine is 3
-azido-3
-deoxytimidine (36.1.26), is synthesized from 1-(2
-deoxy-5
-O-trityl-|?-D-lyxosyl)thymine, which is treated with methansulfonyl chloride in pyridine to make the corresponding mesylate 36.1.24. Replacing the methyl group with an azide group using lithium azide in dimethylformamaide makes the product 36.1.25 with inverted configuration at C3 of the furanosyl ring. Heating this in 80% acetic acid removes the trityl protection, giving zidovudine.

Veterinary Drugs and Treatments

In veterinary medicine, zidovudine may be useful for treating feline immunodeficiency virus (FIV) or feline leukemia virus (FeLV). While zidovudine can reduce the viral load in infected cats and improve clinical signs, it may not alter the natural course of the disease to a great extent.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: absorption reduced by clarithromycin; avoid concomitant use with rifampicin.
Antiepileptics: phenytoin levels may be raised or lowered; concentration possibly increased by valproate (increased risk of toxicity).
Antifungals: concentration increased by fluconazole.
Antivirals: profound myelosuppression with ganciclovir and valganciclovir - avoid if possible; increased risk of granulocytopenia with nevirapine; increased risk of anaemia with ribavirin - avoid; effects of stavudine inhibited - avoid concomitant use; concentration reduced by tipranavir.
Orlistat: absorption possibly reduced by orlistat.
Probenecid: excretion reduced by probenecid, increased risk of toxicity.

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).

Metabolism

Zidovudine is metabolised intracellularly to the antiviral triphosphate. It is also metabolised in the liver, mainly to the inactive glucuronide, and is excreted in the urine as unchanged drug and metabolite.
The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50-80
% of the administered dose eliminated by renal excretion. There is substantial accumulation of this metabolite in renal failure.
Renal clearance of zidovudine greatly exceeds creatinine clearance, indicating that significant tubular secretion takes place.

storage

Room temperature

References

1) Yarchoan?et al. (1989),?Clinical Pharmacology of 3-Azido-2’,3’-Dideoxythymidine (Zidovudine) and Related Dideoxynucleosides; N. Engl. J. Med.?321?726 2) D’Andrea?et al.?(2008),?AZT: an old drug with new perspectives; Curr. Clin. Pharmacol.?3?20 3) Yu?et al. (2015),?Small molecules enhance CRISPR genome editing in pluripotent stem cells; Cell Stem Cell.?16?142