DT-Web

DB02546 - Vorinostat


Identification
Name Vorinostat
Accession Number DB02546 (EXPT02902)
Type small molecule
Description Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA), is a drug currently under investigation for the treatment of cutaneous T cell lymphoma (CTCL), a type of skin cancer, to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. It is the first in a new class of agents known as histone deacetylase inhibitors. A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4 - 4.4 months in earlier studies). Further brain tumor trials are planned in which vorinostat will be combined with other drugs. [Wikipedia]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 264.3202
Groups approved
Monoisotopic Weight 264.147392516
Pharmacology
Indication For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies.
Mechanism of action Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50< 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.
Absorption Not Available
Protein binding 71%
Biotransformation The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by ?-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).
Route of elimination In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat.
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Abarelix Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Amiodarone Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Amitriptyline Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Amoxapine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Apomorphine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Arsenic trioxide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Asenapine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Azithromycin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Chlorpromazine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Cisapride Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Clarithromycin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Clomipramine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Dasatinib Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Desipramine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Disopyramide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Dofetilide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Dolasetron Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Domperidone Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Doxepin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Dronedarone Additive QTc prolongation may occur. Concomitant therapy is contraindicated.
Droperidol Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Erythromycin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Flecainide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Fluconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Fluoxetine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Flupenthixol Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Foscarnet Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Gatifloxacin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Halofantrine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Haloperidol Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ibutilide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Imipramine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Indapamide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Isradipine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Lapatinib Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Levofloxacin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Loxapine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Maprotiline Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Mefloquine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Mesoridazine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Methadone Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Methotrimeprazine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Moxifloxacin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Nilotinib Additive QTc prolongation may occur. Concomitant therapy should be avoided.
Norfloxacin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Nortriptyline Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Octreotide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Pentamidine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Perflutren Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Pimozide Additive QTc prolongation may occur. Concomitant therapy is contraindicated.
Probucol Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Procainamide Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Propafenone Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Protriptyline Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Quetiapine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Quinidine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Quinine Additive QTc prolongation may occur. Concomitant therapy should be avoided.
Ranolazine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Risperidone Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Sotalol Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Sparfloxacin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Sunitinib Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Tacrolimus Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Telithromycin Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Tetrabenazine Additive QTc prolongation may occur. Concomitant therapy should be avoided.
Thioridazine Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Thiothixene Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
Trimipramine Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Voriconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Oral administration with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (Tmax delayed 2.5 hours) compared to the fasted state.

Targets


Histone deacetylase 1
Name Histone deacetylase 1
Gene Name HDAC1
Pharmacological action yes
Actions inhibitor
References
  • Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. - Pubmed
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 1.1951
Histone deacetylase 2
Name Histone deacetylase 2
Gene Name HDAC2
Pharmacological action yes
Actions inhibitor
References
  • Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. - Pubmed
DTHybrid score 0.736
Histone deacetylase 3
Name Histone deacetylase 3
Gene Name HDAC3
Pharmacological action yes
Actions inhibitor
References
  • Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. - Pubmed
DTHybrid score 1.1876
Histone deacetylase 6
Name Histone deacetylase 6
Gene Name HDAC6
Pharmacological action yes
Actions inhibitor
References
  • Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. - Pubmed
DTHybrid score 1.1767
Histone deacetylase 8
Name Histone deacetylase 8
Gene Name HDAC8
Pharmacological action unknown
Actions Not Available
References Not Available
DTHybrid score 2.3282
Acetoin utilization protein
Name Acetoin utilization protein
Gene Name acuC1
Pharmacological action unknown
Actions Not Available
References Not Available
DTHybrid score 1.4453

Predictions


Id Partner name Gene Name Score
6005 Histone deacetylase 7a HDAC7 0.4455
1524 Peptidyl-prolyl cis-trans isomerase A PPIA 0.1197
6700 Peptidyl-prolyl cis-trans isomerase A ppiA 0.1197
2554 Peptidyl-prolyl cis-trans isomerase, mitochondrial PPIF 0.083
16 Adenosine A1 receptor ADORA1 0.0757
485 cGMP-inhibited 3',5'-cyclic phosphodiesterase A PDE3A 0.0673
1178 Adenosine A2a receptor ADORA2A 0.0431
390 Adenosine A3 receptor ADORA3 0.041
1971 cAMP-specific 3',5'-cyclic phosphodiesterase 4A PDE4A 0.0374
4200 Cytochrome P450 1A2 CYP1A2 0.0342
6143 Solute carrier family 22 member 7 SLC22A7 0.0288
6013 Cytochrome P450 2E1 CYP2E1 0.0226
4512 Cytochrome P450 3A4 CYP3A4 0.0216
268 Adenosine A2b receptor ADORA2B 0.0157
6044 Serum paraoxonase/lactonase 3 PON3 0.0147
572 Integrin alpha-L ITGAL 0.0132
4924 Cytochrome P450 2C8 CYP2C8 0.0117
204 cGMP-specific 3',5'-cyclic phosphodiesterase PDE5A 0.0109
4757 Cytochrome P450 2C9 CYP2C9 0.0108
631 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR 0.0105
3387 3-hydroxy-3-methylglutaryl-coenzyme A reductase mvaA 0.0105
4119 Cytochrome P450 2D6 CYP2D6 0.0105
3957 Adenosine deaminase ADA 0.0098
541 cAMP-specific 3',5'-cyclic phosphodiesterase 4B PDE4B 0.0094
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.009
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0084
1898 Cytochrome P450 1B1 CYP1B1 0.0083
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0083
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0074
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0073
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.007
6024 Cytochrome P450 1A1 CYP1A1 0.0067
6107 Cytochrome P450 3A7 CYP3A7 0.0063
4118 Cytochrome P450 3A5 CYP3A5 0.0059
6016 Cytochrome P450 2C19 CYP2C19 0.0056
1588 Multidrug resistance protein 1 ABCB1 0.0053
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