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Showing drug card for Posaconazole (DB01263)

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Creation Date 2007-05-16 17:41:38
Update Date 2009-06-23 18:06:14
Primary Accession Number DB01263
Secondary Accession Number Not Available
Name Posaconazole
Drug Type
  • Approved
  • Investigational
  • Small Molecule
Description Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.
Synonyms
  1. posaconazole
Brand Names
  1. Noxafil
Brand Mixtures Not Available
Chemical IUPAC Name 4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one
Chemical Formula C37H42F2N8O4
Chemical Structure Structure
CAS Registry Number 171228-49-2
InChI Identifier InChI=1/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27?,35-,37-/m0/s1
InChI Key RAGOYPUPXAKGKH-AGDNISCABP
KEGG Drug D02555 Link Image
KEGG Compound Not Available
PubChem Compound 147912 Link Image
PubChem Substance 17396726 Link Image
ChEBI ID Not Available
PharmGKB ID Not Available
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] Not Available
RxList Link http://www.rxlist.com/cgi/generic/noxafil.htm Link Image
PDRhealth Link Not Available
Wikipedia Link http://en.wikipedia.org/wiki/Posaconazole Link Image
FDA Label
Material Safety Data Sheet (MSDS) Not Available
Synthesis Reference Not Available
Average Molecular Weight 700.7774
Monoisotopic Molecular Weight 700.3297
State Solid
Melting Point Not Available
Experimental Water Solubility Insoluble Source: PhysProp
Predicted Water Solubility 1.20e-02 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 5.5 Source: PhysProp
Predicted LogP 4.71 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -4.77 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES CC[C@@H]([C@H](C)O)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OC[C@H]2CO[C@@](C2)(CN2C=NC=N2)C2=C(F)C=C(F)C=C2)C=C1
Canonical SMILES CCC(C(C)O)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OCC2COC(C2)(CN2C=NC=N2)C2=C(F)C=C(F)C=C2)C=C1
Drug Category
  • Antibiotics, Antifungal
  • Trypanocidal Agents
ATC Codes
AHFS Codes Not Available
Indication For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
Pharmacology Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients. There is also limited clinical evidence for its utility in treatment of invasive disease caused by Fusarium species (fusariosis). Two studies published in the January 25, 2007 issue of the New England Journal of Medicine suggest posaconazole may be superior to other triazoles, such as fluconazole or itraconazole, in the prevention of invasive fungal infections, although it may cause more serious side effects.
Mechanism of Action As a triazole antifungal agent, posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14α-demethylase and accumulation of methylated sterol precursors.
Absorption Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.
Toxicity During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator.
Protein Binding Posaconazole is highly protein bound (>98%), predominantly to albumin.
Biotransformation Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Half Life Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).
Dosage Forms
Form Route
Suspension Oral
Patient Information Show Link Image
Contraindications Show Link Image
Interactions Show Link Image
Drug Interactions Not Available
Food Interactions Not Available
Pathways Not Available
General References
  1. Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, Greinix H, Morais de Azevedo W, Reddy V, Boparai N, Pedicone L, Patino H, Durrant S: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007 Jan 25;356(4):335-47. [PubMed Link Image]
  2. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, Helfgott D, Holowiecki J, Stockelberg D, Goh YT, Petrini M, Hardalo C, Suresh R, Angulo-Gonzalez D: Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007 Jan 25;356(4):348-59. [PubMed Link Image]
  3. Wikipedia Link Image
  4. RxList Link Image
Organisms Affected
  • Aspergillis, Candida and other fungi
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 3A4 (CYP3A4)
Targets
  1. Cytochrome P450 51
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 3A4 (CYP3A4)
Enzyme 1 Gene Name CYP3A4
Enzyme 1 SwissProt ID P08684 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >sp|P08684|CP3A4_HUMAN Cytochrome P450 3A4 (EC 1.14.13.67) 
ALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFD
MECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIA
EDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSM
DVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVF
PREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSII
FIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVN
ETLRLFPIAMRLERVCKKDVEINGMFIPKGWVVMIPSYALHRDPKYWTEPEKFLPERFSK
KNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGG
LLQPEKPVVLKVESRDGTVSGA
Drug Target 1 [top]
Target 1 ID 249
Target 1 Name Cytochrome P450 51
Target 1 Synonyms
  1. CYPLI
  2. EC 1.14.13.70
  3. Lanosterol 14-alpha demethylase
  4. P450-14DM
  5. P450-LIA1
  6. Sterol 14- alpha demethylase
Target 1 Gene Name ERG11
Target 1 Protein Sequence >Cytochrome P450 51 
MSATKSIVGEALEYVNIGLSHFLALPLAQRISLIIIIPFIYNIVWQLLYSLRKDRPPLVF
YWIPWVGSAVVYGMKPYEFFEECQKKYGDIFSFVLLGRVMTVYLGPKGHEFVFNAKLADV
SAEAAYAHLTTPVFGKGVIYDCPNSRLMEQKKFVKGALTKEAFKSYVPLIAEEVYKYFRD
SKNFRLNERTTGTIDVMVTQPEMTIFTASRSLLGKEMRAKLDTDFAYLYSDLDKGFTPIN
FVFPNLPLEHYRKRDHAQKAISGTYMSLIKERRKNNDIQDRDLIDSLMKNSTYKDGVKMT
DQEIANLLIGVLMGGQHTSAATSAWILLHLAERPDVQQELYEEQMRVLDGGKKELTYDLL
QEMPLLNQTIKETLRMHHPLHSLFRKVMKDMHVPNTSYVIPAGYHVLVSPGYTHLRDEYF
PNAHQFNIHRWNKDSASSYSVGEEVDYGFGAISKGVSSPYLPFGGGRHRCIGEHFAYCQL
GVLMSIFIRTLKWHYPEGKTVPPPDFTSMVTLPTGPAKIIWEKRNPEQKI
Target 1 Number of Residues 538
Target 1 Molecular Weight 60721
Target 1 Theoretical pI 8.95
Target 1 GO Classification
Function
tetrapyrrole binding
heme binding
binding
ion binding
cation binding
transition metal ion binding
iron ion binding
catalytic activity
oxidoreductase activity
monooxygenase activity
Process
physiological process
metabolism
cellular metabolism
generation of precursor metabolites and energy
electron transport
Component
Not Available
Target 1 General Function Secondary metabolites biosynthesis, transport and catabolism
Target 1 Specific Function Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol
Target 1 Pathways Not Available
Target 1 Reactions
  • obtusifoliol + 3 O2 + 3 NADPH + 3 H+ = 4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + 3 NADP+ + 4 H2O
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • 21-41
Target 1 Essentiality Essential
Target 1 GenBank ID Protein 170946 Link Image
Target 1 UniProtKB/Swiss-Prot ID P10614 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name CP51_YEAST Link Image
Target 1 PDB ID Not Available
Target 1 Cellular Location
  • Membrane
  • multi-pass membrane protein
Target 1 Gene Sequence >1593 bp 
ATGTCTGCTACCAAGTCAATCGTTGGAGAGGCATTGGAATACGTAAACATTGGTTTAAGT
CATTTCTTGGCTTTACCATTGGCCCAAAGAATCTCTTTGATCATAATAATTCCTTTCATT
TACAATATTGTATGGCAATTACTATATTCTTTGAGAAAGGACCGTCCACCTCTAGTGTTT
TACTGGATTCCATGGGTCGGTAGTGCTGTTGTGTACGGTATGAAGCCATACGAGTTTTTC
GAAGAATGTCAAAAGAAATACGGTGATATTTTTTCATTCGTTTTGTTAGGAAGAGTCATG
ACTGTGTATTTAGGACCAAAGGGTCACGAATTTGTCTTCAACGCTAAGTTGGCAGATGTT
TCAGCAGAAGCTGCTTACGCTCATTTGACTACTCCAGTTTTCGGTAAAGGTGTTATTTAC
GATTGTCCAAATTCTAGATTGATGGAGCAAAAGAAGTTTGTTAAGGGTGCTCTAACCAAA
GAAGCCTTCAAGAGCTACGTTCCATTGATTGCTGAAGAAGTGTACAAGTACTTCAGAGAC
TCCAAAAACTTCCGTTTGAATGAAAGAACTACTGGTACTATTGACGTGATGGTTACTCAA
CCTGAAATGACTATTTTCACCGCTTCAAGATCATTATTGGGTAAGGAAATGAGAGCAAAA
TTGGATACCGATTTTGCTTACTTGTACAGTGATTTGGATAAGGGTTTCACTCCAATCAAC
TTCGTCTTCCCTAACTTACCATTGGAACACTATAGAAAGAGAGATCACGCTCAAAAGGCT
ATCTCCGGTACTTACATGTCTTTGATTAAGGAAAGAAGAAAGAACAACGACATTCAAGAC
AGAGATTTGATCGATTCCTTGATGAAGAACTCTACCTACAAGGATGGTGTGAAGATGACT
GATCAAGAAATCGCTAACTTGTTAATTGGTGTCTTAATGGGTGGTCAACATACTTCTGCT
GCCACTTCTGCTTGGATTTTGTTGCACTTGGCTGAAAGACCAGATGTCCAACAAGAATTG
TACGAAGAACAAATGCGTGTTTTGGATGGTGGTAAGAAGGAATTGACCTACGATTTATTA
CAAGAAATGCCATTGTTGAACCAAACTATTAAGGAAACTCTAAGAATGCACCATCCATTG
CACTCTTTGTTCCGTAAGGTTATGAAAGATATGCACGTTCCAAACACTTCTTATGTCATC
CCAGCAGGTTATCACGTTTTGGTTTCTCCAGGTTACACTCATTTAAGAGACGAATACTTC
CCTAATGCTCACCAATTCAACATTCACCGTTGGAACAAAGATTCTGCCTCCTCTTATTCC
GTCGGTGAAGAAGTCGATTACGGTTTCGGTGCCATTTCTAAGGGTGTCAGCTCTCCATAC
TTACCTTTCGGTGGTGGTAGACACAGATGTATCGGTGAACACTTTGCTTACTGTCAGCTA
GGTGTTCTAATGTCCATTTTTATCAGAACATTAAAATGGCATTACCCAGAGGGTAAGACC
GTTCCACCTCCTGACTTTACATCTATGGTTACTCTTCCAACCGGTCCAGCCAAGATCATC
TGGGAAAAGAGAAATCCAGAACAAAAGATCTAA
Target 1 GenBank Gene ID
Target 1 GeneCard ID Not Available
Target 1 GenAtlas ID Not Available
Target 1 HGNC ID Not Available
Target 1 Chromosome Location Not Available
Target 1 Locus Not Available
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Ghaemmaghami S, Huh WK, Bower K, Howson RW, Belle A, Dephoure N, O'Shea EK, Weissman JS: Global analysis of protein expression in yeast. Nature. 2003 Oct 16;425(6959):737-41. [PubMed Link Image]
  2. Ishida N, Aoyama Y, Hatanaka R, Oyama Y, Imajo S, Ishiguro M, Oshima T, Nakazato H, Noguchi T, Maitra US, et al.: A single amino acid substitution converts cytochrome P450(14DM) to an inactive form, cytochrome P450SG1: complete primary structures deduced from cloned DNAS. Biochem Biophys Res Commun. 1988 Aug 30;155(1):317-23. [PubMed Link Image]
  3. Kalb VF, Woods CW, Turi TG, Dey CR, Sutter TR, Loper JC: Primary structure of the P450 lanosterol demethylase gene from Saccharomyces cerevisiae. DNA. 1987 Dec;6(6):529-37. [PubMed Link Image]
  4. Kalb VF, Loper JC, Dey CR, Woods CW, Sutter TR: Isolation of a cytochrome P-450 structural gene from Saccharomyces cerevisiae. Gene. 1986;45(3):237-45. [PubMed Link Image]
  5. Johnston M, Andrews S, Brinkman R, Cooper J, Ding H, Dover J, Du Z, Favello A, Fulton L, Gattung S, et al.: Complete nucleotide sequence of Saccharomyces cerevisiae chromosome VIII. Science. 1994 Sep 30;265(5181):2077-82. [PubMed Link Image]
Target 1 Drug References
  1. Li X, Brown N, Chau AS, Lopez-Ribot JL, Ruesga MT, Quindos G, Mendrick CA, Hare RS, Loebenberg D, DiDomenico B, McNicholas PM: Changes in susceptibility to posaconazole in clinical isolates of Candida albicans. J Antimicrob Chemother. 2004 Jan;53(1):74-80. Epub 2003 Dec 4. [PubMed Link Image]
  2. Chau AS, Mendrick CA, Sabatelli FJ, Loebenberg D, McNicholas PM: Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles. Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31. [PubMed Link Image]
  3. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed Link Image]
  4. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.