Zalcitabine

Identification

Summary

Zalcitabine is a dideoxynucleoside used to treat HIV.

Generic Name
Zalcitabine
DrugBank Accession Number
DB00943
Background

A dideoxynucleoside compound in which the 3'-hydroxyl group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of 5' to 3' phosphodiester linkages, which are needed for the elongation of DNA chains, thus resulting in the termination of viral DNA growth. The compound is a potent inhibitor of HIV replication at low concentrations, acting as a chain-terminator of viral DNA by binding to reverse transcriptase. Its principal toxic side effect is axonal degeneration resulting in peripheral neuropathy.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 211.2178
Monoisotopic: 211.095691297
Chemical Formula
C9H13N3O3
Synonyms
  • 2',3'-Dideoxycytidine
  • 4-amino-1-[(2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl]pyrimidin-2(1H)-one
  • DDC
  • DDCYD
  • Dideoxycytidine
  • Zalcitabine
External IDs
  • RO 24-2027/000
  • RO-24-2027/000
  • RO-24-2027000
  • RO-242027000

Pharmacology

Indication

For the treatment of Human immunovirus (HIV) infections in conjunction with other antivirals.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Zalcitabine is an analog of 2'-deoxycytidine that is pharmacologically related to but structurally different from other nucleotide reverse transcriptase inhibitors (NRTIs). Zalcitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.

Mechanism of action

Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Within cells, zalcitabine is converted to its active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the sequential action of cellular enzymes. ddCTP interferes with viral RNA-directed DNA polymerase (reverse transcriptase) by competing for utilization of the natural substrate deoxycytidine 5'-triphosphate (dCTP), as well as incorpating into viral DNA. Due to it's lack of a 3'-OH group, the formation of a 5' to 3' phosphodiester linkage that is necessary for DNA chain elongation is inhibited, thus leading to the termination of viral DNA growth.

TargetActionsOrganism
AReverse transcriptase/RNaseH
inhibitor
Human immunodeficiency virus 1
Absorption

Bioavailability is over 80% following oral administration.

Volume of distribution
  • 0.304 to 0.734 L/kg
Protein binding

Less than 4%

Metabolism

Zalcitabine is not reported to undergo significant hepatic metabolism; it is mainly phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. The concentration of zalcitabine triphosphate remains low for quantitative detection and measurement in the plasma following administration of therapeutic doses Label.

Route of elimination

Renal excretion of unchanged drug appears to be the primary route of elimination, accounting for approximately 80% of an intravenous dose and 60% of an orally administered dose within 24 hours after dosing (n=19). Renal clearance exceeds glomerular filtration rate suggesting renal tubular secretion contributes to the elimination of zalcitabine by the kidneys.

Half-life

2 hours

Clearance
  • 285 mL/min [HIV-infected patients receiving 1.5 mg IV infusion for 1 hour]
Adverse Effects
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Toxicity

Acute overdose: Inadvertent pediatric overdoses have occurred with doses up to 1.5 mg/kg zalcitabine. Chronic overdose: in an initial dose-finding study in which zalcitabine was administered at doses 25 times (0.25 mg/kg every 8 hours) the currently recommended dose, one patient discontinued zalcitabine after 1½ weeks of treatment subsequent to the development of a rash and fever.

Pathways
PathwayCategory
Zalcitabine Action PathwayDrug action
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcetazolamideThe excretion of Zalcitabine can be decreased when combined with Acetazolamide.
Acetylsalicylic acidThe excretion of Zalcitabine can be decreased when combined with Acetylsalicylic acid.
AcyclovirThe excretion of Zalcitabine can be decreased when combined with Acyclovir.
Adefovir dipivoxilThe excretion of Zalcitabine can be decreased when combined with Adefovir dipivoxil.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Zalcitabine.
Food Interactions
  • Avoid multivalent ions. Magnesium and aluminum containing products can reduce the absorption of this medication.
  • Take on an empty stomach. Take at least 1 hour before or 2 hours after meals.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
HividTablet, film coated0.75 mg/1OralPhysicians Total Care, Inc.1992-06-192007-08-21US flag
HividTablet, film coated0.75 mg/1OralGenentech, Inc.1992-06-192009-06-18US flag
HividTablet, film coated0.375 mg/1OralGenentech, Inc.1992-06-192009-06-18US flag
Hivid Tab 0.375mgTablet.375 mgOralHoffmann La Roche1992-12-312003-07-30Canada flag
Hivid Tab 0.75 mgTablet.75 mgOralHoffmann La Roche1992-12-312006-07-25Canada flag

Categories

ATC Codes
J05AF03 — Zalcitabine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyrimidine 2',3'-dideoxyribonucleosides. These are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at positions 2 and 3.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Pyrimidine nucleosides
Sub Class
Pyrimidine 2',3'-dideoxyribonucleosides
Direct Parent
Pyrimidine 2',3'-dideoxyribonucleosides
Alternative Parents
Pyrimidones / Aminopyrimidines and derivatives / Imidolactams / Hydropyrimidines / Tetrahydrofurans / Heteroaromatic compounds / Oxacyclic compounds / Azacyclic compounds / Primary amines / Primary alcohols
show 3 more
Substituents
Alcohol / Amine / Aminopyrimidine / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine / Imidolactam / Organic nitrogen compound
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrimidine 2',3'-dideoxyribonucleoside (CHEBI:10101)
Affected organisms
  • Human Immunodeficiency Virus

Chemical Identifiers

UNII
6L3XT8CB3I
CAS number
7481-89-2
InChI Key
WREGKURFCTUGRC-POYBYMJQSA-N
InChI
InChI=1S/C9H13N3O3/c10-7-3-4-12(9(14)11-7)8-2-1-6(5-13)15-8/h3-4,6,8,13H,1-2,5H2,(H2,10,11,14)/t6-,8+/m0/s1
IUPAC Name
4-amino-1-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one
SMILES
NC1=NC(=O)N(C=C1)[C@H]1CC[C@@H](CO)O1

References

General References
  1. Shelton MJ, O'Donnell AM, Morse GD: Zalcitabine. Ann Pharmacother. 1993 Apr;27(4):480-9. [Article]
  2. Devineni D, Gallo JM: Zalcitabine. Clinical pharmacokinetics and efficacy. Clin Pharmacokinet. 1995 May;28(5):351-60. [Article]
Human Metabolome Database
HMDB0015078
KEGG Drug
D00412
KEGG Compound
C07207
PubChem Compound
24066
PubChem Substance
46507879
ChemSpider
22498
BindingDB
50145605
RxNav
3363
ChEBI
10101
ChEMBL
CHEMBL853
ZINC
ZINC000000039906
Therapeutic Targets Database
DNC000527
PharmGKB
PA451950
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Zalcitabine
FDA label
Download (244 KB)
MSDS
Download (36 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Pharmacoeconomics

Manufacturers
  • Hoffmann la roche inc
Packagers
  • Murfreesboro Pharmaceutical Nursing Supply
  • Pharmaceutical Utilization Management Program VA Inc.
  • Physicians Total Care Inc.
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral0.375 mg/1
Tablet, film coatedOral0.75 mg/1
TabletOral.375 mg
TabletOral.75 mg
TabletOral0.75 mg
TabletOral0.375 mg
Tablet, film coatedOral0.75 mg
Prices
Unit descriptionCostUnit
Hivid 0.75 mg tablet2.84USD tablet
Hivid 0.375 mg tablet2.27USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)217-218 °CPhysProp
water solubility7.64E+004 mg/L (at 25 °C)PHYSICIANS DESK REFERENCE (2001)
logP-1.30SANGSTER (1993)
Predicted Properties
PropertyValueSource
Water Solubility7.05 mg/mLALOGPS
logP-1.3ALOGPS
logP-1.2Chemaxon
logS-1.5ALOGPS
pKa (Strongest Acidic)14.67Chemaxon
pKa (Strongest Basic)4.48Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area88.15 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity52.24 m3·mol-1Chemaxon
Polarizability20.92 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9972
Blood Brain Barrier+0.9761
Caco-2 permeable-0.7931
P-glycoprotein substrateNon-substrate0.7746
P-glycoprotein inhibitor INon-inhibitor0.937
P-glycoprotein inhibitor IINon-inhibitor0.9171
Renal organic cation transporterNon-inhibitor0.8163
CYP450 2C9 substrateNon-substrate0.8286
CYP450 2D6 substrateNon-substrate0.8493
CYP450 3A4 substrateNon-substrate0.5762
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8893
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9213
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.8626
BiodegradationNot ready biodegradable0.8721
Rat acute toxicity2.0606 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.925
hERG inhibition (predictor II)Non-inhibitor0.875
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-005c-9600000000-2b4de4867a39d5e3055b
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-03di-0190000000-5d3365f648d5f5675ab9
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-066r-2900000000-843d28df71eab94652c3
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0a4l-7900000000-628c9e8f6a131581a8d4
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-9200000000-60a00651a71121843a19
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-0006-9000000000-237a0c1094225974a6e8
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03di-0910000000-95a2a7845a54a61d7c15
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03di-0900000000-345deba429b644c7b4f5
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03di-0900000000-6aaba2f2eeb001628ab2
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03di-5900000000-03b881f85c17ccbe5295
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-01ot-9300000000-2896ce7406bb834c001a
LC-MS/MS Spectrum - LC-ESI-IT , positiveLC-MS/MSsplash10-03di-0900000000-056961b8bc4067346530
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-0900000000-9c4b3aee044ce7956a96
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0970000000-54526a661f3d174f6656
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-2900000000-891c2cbbddfdec8fdc00
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-9200000000-5046c313f3dfd83dc383
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0i01-9200000000-952eba834ff4e8d0ee5d
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-9500000000-0aaf211e0a22b65a6a24
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-149.4572638
predicted
DarkChem Lite v0.1.0
[M-H]-149.3093638
predicted
DarkChem Lite v0.1.0
[M-H]-149.4220638
predicted
DarkChem Lite v0.1.0
[M-H]-144.52248
predicted
DeepCCS 1.0 (2019)
[M+H]+150.7527638
predicted
DarkChem Lite v0.1.0
[M+H]+150.5403638
predicted
DarkChem Lite v0.1.0
[M+H]+150.5553638
predicted
DarkChem Lite v0.1.0
[M+H]+146.91806
predicted
DeepCCS 1.0 (2019)
[M+Na]+149.2785638
predicted
DarkChem Lite v0.1.0
[M+Na]+149.5527638
predicted
DarkChem Lite v0.1.0
[M+Na]+149.5601638
predicted
DarkChem Lite v0.1.0
[M+Na]+152.90862
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Rna-dna hybrid ribonuclease activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72547
Uniprot Name
Reverse transcriptase/RNaseH
Molecular Weight
65223.615 Da
References
  1. Devineni D, Gallo JM: Zalcitabine. Clinical pharmacokinetics and efficacy. Clin Pharmacokinet. 1995 May;28(5):351-60. [Article]
  2. Adkins JC, Peters DH, Faulds D: Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection. Drugs. 1997 Jun;53(6):1054-80. [Article]
  3. De Clercq E: Emerging anti-HIV drugs. Expert Opin Emerg Drugs. 2005 May;10(2):241-73. [Article]

Enzymes

Details
1. Deoxycytidine kinase
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based...
Gene Name
DCK
Uniprot ID
P27707
Uniprot Name
Deoxycytidine kinase
Molecular Weight
30518.315 Da
References
  1. Rossi L, Serafini S, Schiavano GF, Casabianca A, Vallanti G, Chiarantini L, Magnani M: Metabolism, mitochondrial uptake and toxicity of 2', 3'-dideoxycytidine. Biochem J. 1999 Dec 15;344 Pt 3:915-20. [Article]
  2. Kitos TE, Tyrrell DL: Intracellular metabolism of 2',3'-dideoxynucleosides in duck hepatocyte primary cultures. Biochem Pharmacol. 1995 May 11;49(9):1291-302. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Bocedi A, Notaril S, Narciso P, Bolli A, Fasano M, Ascenzi P: Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H: Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000 Sep;294(3):844-9. [Article]
  2. VanWert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulf...
Gene Name
SLC22A7
Uniprot ID
Q9Y694
Uniprot Name
Solute carrier family 22 member 7
Molecular Weight
60025.025 Da
References
  1. Morita N, Kusuhara H, Sekine T, Endou H, Sugiyama Y: Functional characterization of rat organic anion transporter 2 in LLC-PK1 cells. J Pharmacol Exp Ther. 2001 Sep;298(3):1179-84. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Nucleoside transmembrane transporter activity
Specific Function
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR...
Gene Name
SLC29A1
Uniprot ID
Q99808
Uniprot Name
Equilibrative nucleoside transporter 1
Molecular Weight
50218.805 Da
References
  1. Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD: Transport of antiviral 3'-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol. 2001 Apr-Jun;18(2):161-7. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Nucleoside transmembrane transporter activity
Specific Function
Mediates equilibrative transport of purine, pyrimidine nucleosides and the purine base hypoxanthine. Very less sensitive than SLC29A1 to inhibition by nitrobenzylthioinosine (NBMPR), dipyridamole, ...
Gene Name
SLC29A2
Uniprot ID
Q14542
Uniprot Name
Equilibrative nucleoside transporter 2
Molecular Weight
50112.335 Da
References
  1. Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD: Transport of antiviral 3'-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol. 2001 Apr-Jun;18(2):161-7. [Article]

Drug created at June 13, 2005 13:24 / Updated at February 02, 2024 22:46