Identification

Name
Zalcitabine
Accession Number
DB00943  (APRD00562)
Type
Small Molecule
Groups
Approved, Investigational
Description

A dideoxynucleoside compound in which the 3'-hydroxyl group on the sugar moiety has been replaced by a hydrogen.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. [PubChem]

Structure
Thumb
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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
HividTablet, film coated0.75 mg/1OralPhysicians Total Care, Inc.1992-06-192007-08-21Us
HividTablet, film coated0.75 mg/1OralGenentech, Inc.1992-06-192009-06-18Us
HividTablet, film coated0.375 mg/1OralGenentech, Inc.1992-06-192009-06-18Us
Hivid Tab 0.375mgTablet.375 mgOralHoffmann La Roche1992-12-312003-07-30Canada
Hivid Tab 0.75 mgTablet.75 mgOralHoffmann La Roche1992-12-312006-07-25Canada
International/Other Brands
HIVID
Categories
UNII
6L3XT8CB3I
CAS number
7481-89-2
Weight
Average: 211.2178
Monoisotopic: 211.095691297
Chemical Formula
C9H13N3O3
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

Pharmacology

Indication

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

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]
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.

Affected organisms
  • Human Immunodeficiency Virus
Pathways
PathwayCategory
Zalcitabine Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenThe excretion of Zalcitabine can be decreased when combined with Acetaminophen.
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.
AlprostadilThe excretion of Zalcitabine can be decreased when combined with Alprostadil.
Aminohippuric acidThe excretion of Zalcitabine can be decreased when combined with Aminohippuric acid.
AminophenazoneThe excretion of Zalcitabine can be decreased when combined with Aminophenazone.
AmoxicillinThe excretion of Zalcitabine can be decreased when combined with Amoxicillin.
AntipyrineThe excretion of Zalcitabine can be decreased when combined with Antipyrine.
Food Interactions
  • Do not take calcium, aluminium, magnesium or iron supplements within 2 hours of taking this medication.
  • Take on empty stomach: 1 hour before or 2 hours after meals.

References

General References
  1. Shelton MJ, O'Donnell AM, Morse GD: Zalcitabine. Ann Pharmacother. 1993 Apr;27(4):480-9. [PubMed:8097417]
  2. Devineni D, Gallo JM: Zalcitabine. Clinical pharmacokinetics and efficacy. Clin Pharmacokinet. 1995 May;28(5):351-60. [PubMed:7614775]
External Links
Human Metabolome Database
HMDB0015078
KEGG Drug
D00412
KEGG Compound
C07207
PubChem Compound
24066
PubChem Substance
46507879
ChemSpider
22498
BindingDB
50145605
ChEBI
10101
ChEMBL
CHEMBL853
Therapeutic Targets Database
DNC000527
PharmGKB
PA451950
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Zalcitabine
ATC Codes
J05AF03 — Zalcitabine
FDA label
Download (244 KB)
MSDS
Download (36 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections4
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Kaposi s Sarcoma (KS)1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections15
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Progressive Multifocal Leukoencephalopathy1
2, 3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections7
4CompletedTreatmentHemophilia A / Human Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections9

Pharmacoeconomics

Manufacturers
  • Hoffmann la roche inc
Packagers
  • Murfreesboro Pharmaceutical Nursing Supply
  • Pharmaceutical Utilization Management Program VA Inc.
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
Tablet, film coatedOral0.375 mg/1
Tablet, film coatedOral0.75 mg/1
TabletOral.375 mg
TabletOral.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)0.18ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area88.15 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity52.24 m3·mol-1ChemAxon
Polarizability20.86 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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
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

Taxonomy

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
Pyrimidine 2',3'-dideoxyribonucleoside / Aminopyrimidine / Pyrimidone / Hydropyrimidine / Pyrimidine / Imidolactam / Heteroaromatic compound / Tetrahydrofuran / Oxacycle / Azacycle
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
pyrimidine 2',3'-dideoxyribonucleoside (CHEBI:10101)

Targets

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. [PubMed:7614775]
  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. [PubMed:9179531]

Enzymes

Details
1. Deoxycytidine kinase
Kind
Protein
Organism
Human
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. [PubMed:10585881]
  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. [PubMed:7763311]

Carriers

Kind
Protein
Organism
Human
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. [PubMed:15814459]

Transporters

Kind
Protein
Organism
Human
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. [PubMed:10945832]
  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. [PubMed:19953504]
Kind
Protein
Organism
Human
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. [PubMed:11504818]
Kind
Protein
Organism
Human
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. [PubMed:11463208]
Kind
Protein
Organism
Human
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. [PubMed:11463208]

Drug created on June 13, 2005 07:24 / Updated on December 14, 2018 12:39