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Purity: ≥98%
Zidovudine (also known as ZDV, Azidothymidine; Retrovir; Zidovudinum, NSC 602670) is a nucleoside analogue reverse transcriptase inhibitor (NRTI) which used to treat and prevent HIV. Zidovudine is the first effective agent for the management of HIV-1 infection and is approved by FDA as a drug for AIDs in 1987. As a nucleoside analogue, zidovudine inhibits the activity of the reverse transcriptase with its triphosphate structure. It can also be used to prevent HIV transmission, such as from mother to child during the period of birth or after a needle stick injury. Used by itself in HIV-infected patients, AZT slows HIV replication in patients, but does not stop it entirely.
| Targets |
HIV reverse transcriptase (NRTI)
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| ln Vitro |
With EC50s of 17, 1311, 8, and 5 nM, respectively, zidovudine inhibits SVG, primary human fetal astrocytes (PFA), peripheral blood mononuclear cells (PBMC), and monocyte-derived macrophages (MDM). With EC90 values of 0.205 μM, 44.157 μM, 0.481 μM, and 0.219 μM, respectively, zidovudine inhibits SVG, PFA, PBMC, and MDM [1]. CRISPR/Cas9 genome editing has emerged as a dependable and efficient technique for precisely altering specific regions of the genome in living cells. CXCR4 is regarded as a key therapeutic target for AIDS since it functions as a coreceptor for HIV-1 infection. By attaching itself to the envelope protein gp120, CXCR4 facilitates viral entrance into human CD4+ cells. CRISPR/Cas9-mediated genome editing effectively disrupts the human CXCR4 gene, leading to HIV-1 resistance in human primary CD4+ T cells. High specificity and minimal off-target effects are displayed by Cas9-mediated CXCR4 ablation, which has no effect on cell division or proliferation [2].
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| ln Vivo |
In wild-type mice, laser-induced choroidal neovascularization (CNV) was inhibited by NRTIs lamivudine (3TC), zidovudine (AZT), or abacavir (ABC) in comparison to the PBS vehicle. Day 3 following laser injury marked the peak of mean VEGF-A levels in the RPE/choroid. The eyes of mice treated with 3TC, AZT, and ABC had significantly lower levels of this protein than the wild-type mice's control eyes, but not the P2rx7-/- mice. [3].
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| Enzyme Assay |
Production and quantitation of Env-pseudotyped luciferase reporter viruses[1]
Env-pseudotyped luciferase reporter viruses were produced by transfection of 293T cells with pCMVΔP1ΔenvpA, pHIV-1Luc, and either pcDNA3-VSVg or pSVIII-YU2 Env plasmids using Lipofectamine 2000 (Invitrogen) at a ratio of 1∶3∶1, as described previously. Viruses pseudotyped with the CCR5-using HIV-1 YU-2 envelope glycoproteins were used for infections of PBMC and MDM, whereas SVG cells and PFA were infected with viruses pseudotyped with the vesicular stomatitis virus G protein (VSV-G) in order to achieve sufficient levels of viral entry for the inhibition assays. The supernatants containing virus pseudotypes were harvested 48 h later, filtered through 0.45 µm filters, titrated on each of the different cell types (TCID50 values were calculated), and stored at −80°C. |
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| Cell Assay |
Cell viability assay[1]
ARV cytotoxicity was assessed in all cell types at 72 h post-drug exposure using the CellTitre-Glo Luminescent Cell Viability Assay (Promega, USA), according to the manufacturer's protocol.[1] Virus inhibition assays[1] Assays were performed in all cell types in the presence of titrating concentrations of ARV. 5,000 SVG, 2,500 PFA, 200,000 PBMC, or 50,000 MDM cells/well were seeded into triplicate wells of 96-well plates. Twenty-four hours later, the culture medium was removed and replaced with medium containing the ARV or DMSO (0.5% vol/vol), and equivalent TCID50 infectious units of luciferase reporter virus were added to the cells. After a 16 h incubation at 37°C, the initial viral inoculum was removed and replaced with culture medium containing the same ARV or DMSO (0.5% vol/vol) concentrations. At 72 h post infection, the medium was aspirated, the cells were lysed and HIV-1 infection measured using the Luciferase Assay System (Promega) according to manufacturer's instructions. Luminescence was measured using a FLUOStar Optima microplate reader (BMG Labtech, Germany). Inhibition curves and the 50% (EC50) and 90% (EC90) effective concentrations were determined by nonlinear regression analysis as previously described, using GraphPad Prism software.[1] |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
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. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV. Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age] 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age] 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age]. The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine. In patients with impaired renal function, plasma concentrations of zidovudine may be increased and the half-life prolonged. In one study in adults with impaired renal function (creatinine clearances ranging from 6-31 ml/minute) without HIV infections beta half life of zidovudine averaged 1.4 hours and was similar to that reported for adults with HIV infections who had normal renal function. However, the beta half life of glucuronide in these adults with impaired renal function averaged 8 hours and was considerably prolonged compared with that reported for adults with HIV infections who had normal renal function. In one study in adults with hemophilia and HIV infections who had elevated serum concentrations of aspartate aminotransferase (serum glutamic-oxaloacetic transaminase), alanine aminotransferase (serum glutamic-pyruvic transaminase), pharmacokinetics of zidovudine after a single 300 mg oral dose showed considerable interindividual variation. Following oral administration of zidovudine in patients with HIV infections, 63-95% of the dose is excreted in urine; approximately 14-18% of the dose is excreted as unchanged zidovudine and 72-74% is excreted as zidovudine 5'-O-glucuronide within 6 hours. Following iv administration of the drug in adults or children with HIV infections, approximately 18-29% of the dose is excreted in urine as unchanged drug and 45-60% is excreted as zidovudine 5'-O-glucuronide within 6 hours. Zidovudine and 3'-azodp-3'-deoxy-5'-O-beta-d-glucopyranuronosylthymidine are eliminated principally in urine via both glomerular filtration and tubular secretion. Following oral or IV administration in adults with HIV infection, total body clearance of zidovudine averages 1.6 l/hr per kg (range: 0.8-2.7 l/hr per kg) and renal clearance of the drug averages 0.34 l/hr per kg. In children 3 months to 12 years of age, the total body clearance averaged 1.85 l/hr per kg. In one limited study in neonates and infants younger than 3 months of age, total body clearance of the drug averaged 0.65 l/hr per kg in those 14 days of age or younger and 1.14 l/hr per kg in those older than 14 days of age. Zidovudine is rapidly metabolized via glucuronidation in the liver to zidovudine 5'-O-glucuronide (GAZT); the metabolite has an apparent elimination half life of 1 hour (range: 0.6-1.7 hours). Zidovudine 5'-O-glucuronide does not appear to have antiviral activity against HIV. For more Absorption, Distribution and Excretion (Complete) data for ZIDOVUDINE (21 total), please visit the HSDB record page. Metabolism / Metabolites 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). Zidovudine is rapidly metabolized via glucuronidation in the liver principally to 3-azido-3-deoxy-5-O-beta-d-glucopyranuronosylthymidine (GZDV; formerly GAZT); zidovudine is also metabolized to GZDV in renal microsomes. GZDV has an apparent elimination half-life of 1 hour (range: 0.6-1.7 hours) and does not appear to have antiviral activity against HIV. In addition, two other hepatic metabolites of zidovudine have been identified as 3-amino-3-deoxythymidine (AMT) and its glucuronide derivative (GAMT). Intracellularly, in both virus-infected and uninfected cells, zidovudine is converted to zidovudine monophosphate by cellular thymidine kinase; the monophosphate derivative is phosphorylated to zidovudine diphosphate via cellular dTMP kinase (thymidylate kinase) and then to zidovudine triphosphate via other cellular enzymes. Intracellular (host cell) conversion of zidovudine to the triphosphate derivative is necessary for the antiviral activity of the drug. Activation for antibacterial action, however, does not depend on phosphorylation within host cells but rather depends on conversion within bacterial cells. The mechanisms of intestinal mucosal transport and metabolism of zidovudine and other thymidine analogs were studied. No zidovudine metabolites appeared in any part of the gastrointestinal tract. Other thymidine analogs were rapidly metabolized in the upper gastrointestinal tract, but not in the colon. 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). Route of Elimination: As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV. Half Life: Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours) Biological Half-Life Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours) The plasma half-life of zidovudine in adults averages approximately 0.53 hours following oral or IV administration. Following IV administration of zidovudine in adults or children, plasma concentrations of the drug appear to decline in a biphasic manner. Half-life in adults is less than 10 minutes in the initial phase and 1 hour in the terminal phase. Following IV administration over 1 hour of a single 80-, 120-, or 160-mg/sq m , dose in children 1-13 years of age with symptomatic HIV infection, the alpha half-life of zidovudine averaged 0.16-0.25 hours and the beta half-life averaged 1-1.7 hours. Plasma half-life of zidovudine generally is longer in neonates than in older children and adults but decreases with neonatal maturity. In one limited study in neonates and infants younger than 3 months of age, plasma half-life of zidovudine averaged 3.1 hours in those 14 days of age or younger and 1.9 hours in those older than 14 days of age. In a study in premature neonates (26-32 weeks gestation; birthweight 0.7-1.9 kg), the serum half-life of zidovudine averaged 7.3 hours at an average postnatal age of 6.3 days and averaged 4.4 hours at an average postnatal age of 17.7 days. The value for half-life of zidovudine is 1-2 hr. |
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| Toxicity/Toxicokinetics |
Toxicity Summary
Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5ду_-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase ‘± and ‘_. Toxicity Data Male rat(po): LD50 = 3.1 g/kg Female rat(po): LD50 = 3.7 g/kg Male mice: LD50 = 3.6 g/kg Female mice(po): LD50 = 3.1 g/kg LD50 is 3084 mg/kg (orally in mice). Interactions Concomitant use of probenecid may produce substantially higher and prolonged serum concentrations of zidovudine. In at least one study, concomitant use of acetaminophen reportedly resulted in an increased risk of granulocytopenia in patients receiving zidovudine; this potentiation of hematologic toxicity appeared to correlate with the duration of acetaminophen use. Neurotoxicity (profound drowsiness and lethargy), which recurred on rechallenge, has been reported in at least one HIV-infected patient who received acyclovir and zidovudine concomitantly. Neurotoxicity was evident within 30-60 days after initiation of IV acyclovir therapy, persisted with some improvement when acyclovir was administered orally, and resolved following discontinuance of acyclovir in this patient. Acyclovir and zidovudine have been used concomitantly in other HIV-infected patients without evidence of increased toxicity. Although the clinical importance is unclear, there is some evidence that acyclovir may potentiate the antiretroviral effect of zidovudine in vitro; acyclovir alone has only minimal antiretroviral activity. Both ganciclovir and zidovudine alone produce direct, dose-dependent inhibitory effects on myeloid and erythroid progenitor cells, and combined use of the drugs increases the risk of hematologic toxicity and may result in additive or synergistic myelotoxic effects. In several studies in patients with AIDS and cytomegalovirus infections, profound, intolerable myelosuppression, evidenced principally as severe neutropenia, occurred in all patients receiving ganciclovir (5 mg/kg iv 1-4 times daily) concomitantly with zidovudine (200 mg orally every 4 hours); anemia also occurred in many of these patients. Severe hematologic toxicity, which required a reduction in zidovudine dosage, also occurred in more than 80% of patients receiving ganciclovir (5 mg/kg iv 1-2 times daily) concomitantly with zidovudine (100 mg orally every 4 hours). For more Interactions (Complete) data for ZIDOVUDINE (18 total), please visit the HSDB record page. Non-Human Toxicity Values LD50 Rat iv > 750 mg/kg LD50 Mice iv > 3000 mg/kg |
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| Additional Infomation |
Therapeutic Uses
Anti-HIV Agents; Antimetabolites; Antimetabolites, Antineoplastic; Reverse Transcriptase Inhibitors Zidovudine is indicated in combination with other antiretroviral agents for the treatment of HIV infection. ... /Included in US product labeling/ Zidovudine is indicated for the prevention of mother-to-child transmission of HIV-1 infection as part of a regimen that includes oral zidovudine beginning between 14 and 34 weeks gestation, continuous intravenous infusion of zidovudine during labor, and administration of zidovudine syrup to the neonate for the first 6 weeks of life. However, transmission to infants may still occur in some cases despite the use of this regimen. /Included in US product labeling/ Zidovudine has been used prophylactically in health care workers at risk of acquiring HIV infection after occupational exposure to the virus. Risk of transmission from a single needlestick is approximately 0.3%. Efficacy, and optimal dose and duration of prophylactic treatment are unknown at this time; however, HIV infection has occurred in persons who received zidovudine prophylaxis after a needlestick or other parenteral exposure. /NOT included in US product labeling/ For more Therapeutic Uses (Complete) data for ZIDOVUDINE (7 total), please visit the HSDB record page. Drug Warnings Adverse systemic effects reported with IV zidovudine are similar to those reported with oral zidovudine. However, clinical experience with IV zidovudine has been more limited than experience with oral zidovudine and the drug has generally been administered IV only for short periods of time. Long-term IV zidovudine therapy (i.e., longer than 2-4 weeks) has not been evaluated in adults and may enhance adverse hematologic effects. The most common adverse effects of zidovudine are hematologic effects (i.e., anemia, neutropenia), nausea, and headache. Because HIV-infected patients receiving zidovudine generally have serious underlying disease with multiple baseline symptomatology and clinical abnormalities and because many adverse effects that occurred in zidovudine-treated patients also occurred in patients receiving placebo, many reported effects may not be directly attributable to zidovudine. The frequency and severity of adverse effects associated with use of zidovudine in adults are greater in patients with more advanced disease at the time of initiation of therapy. In one study in asymptomatic patients receiving 100 mg of the drug orally 5 times daily for an average of longer than 1 year (range: 4 months to 2 years), only nausea occurred more frequently in patients receiving zidovudine than in those receiving placebo. Adverse effects reported with use of zidovudine in women, IV drug users, and racial minorities are similar to those reported with use of the drug in white males. Four patients with the acquired immunodeficiency syndrome, and a history of Pneumocystis carinii pneumonia developed severe pancytopenia (hemoglobin, less than 85 g/l; granulocytes, less than or equal to 0.5 X 10(9)/L; platelets, less than or equal to 30 X 10(9)/L) 12 to 17 weeks after the initiation of azidothymidine (AZT) therapy. The bone marrow was markedly hypocellular in three patients and moderately hypocellular in the fourth. Partial bone marrow recovery was documented within 4 to 5 weeks in three patients, but no marrow recovery has yet occurred in one patient during the more than 6 months since AZT treatment was discontinued. Hematologic toxicity is causally related to zidovudine therapy, being directly related to dosage and duration of therapy with the drug, and has been reported most frequently in patients with advanced symptomatic HIV infection or low pretreatment hemoglobin concentrations, neutrophil counts, and helper/inducer (CD4+, T4+) T-cell counts. Patients with low serum folate or vitamin B12 concentrations may be at increased risk for developing bone marrow toxicity during zidovudine therapy. There also are limited data suggesting that bone marrow of patients with fulminant acquired immunodeficiency syndrome (AIDS) may be more sensitive to zidovudine-induced toxicity than that of patients with less advanced disease (e.g., AIDS-related complex (ARC)). For more Drug Warnings (Complete) data for ZIDOVUDINE (43 total), please visit the HSDB record page. Pharmacodynamics 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. |
| Molecular Formula |
C10H13N5O4
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| Molecular Weight |
267.24
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| Exact Mass |
267.096
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| Elemental Analysis |
C, 44.94; H, 4.90; N, 26.21; O, 23.95
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| CAS # |
30516-87-1
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| Related CAS # |
117675-21-5 (glucuronide); 106060-89-3 (diphosphate); 92586-35-1 (triphosphate)
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| PubChem CID |
35370
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| Appearance |
White to off-white solid
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| Melting Point |
113-115 °C(lit.)
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| Index of Refraction |
47 ° (C=1, H2O)
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| LogP |
-0.53
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
19
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| Complexity |
484
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O=C(C(C)=CN1[C@@H](C2)O[C@@H]([C@H]2N=[N+]=[N-])CO)NC1=O
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| InChi Key |
HBOMLICNUCNMMY-XLPZGREQSA-N
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| InChi Code |
InChI=1S/C10H13N5O4/c1-5-3-15(10(18)12-9(5)17)8-2-6(13-14-11)7(4-16)19-8/h3,6-8,16H,2,4H2,1H3,(H,12,17,18)/t6-,7+,8+/m0/s1
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| Chemical Name |
1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.35 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (9.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 18 mg/mL (67.4 mM) Solubility in Formulation 5: 20 mg/mL (74.84 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.7420 mL | 18.7098 mL | 37.4195 mL | |
| 5 mM | 0.7484 mL | 3.7420 mL | 7.4839 mL | |
| 10 mM | 0.3742 mL | 1.8710 mL | 3.7420 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Early Infant HIV Treatment in Botswana
CTID: NCT02369406
Phase: Phase 2/Phase 3 Status: Active, not recruiting
Date: 2023-11-09
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Products are for research use only; We do not sell to patients
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