Chemical: Drug
isosorbide dinitrate

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last updated 10/25/2013

1. FDA Label for hydralazine,isosorbide dinitrate and NAT2

Informative PGx

Summary

Isosorbide dinitrate and hydralazine hydrochloride (Bidil) is metabolized by acetylation, and individuals who are 'fast acetylators' may have increased exposure to the drug, whereas individuals who are 'slow acetylators' may have increased drug bioavailability. Acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene.

Annotation

Isosorbide dinitrate and hydralazine hydrochloride (Bidil) is indicated for the treatment of heart failure in self-identified Black patients, as an adjunct therapy to standard therapy. The genetics behind the mode of efficacy related to this population of patients is to our knowledge currently unknown.

NAT1 and NAT2 genes are biomarkers listed for the Isosorbide dinitrate and Hydralazine drug label in the FDA Table of Pharmacogenomic Biomarkers in Drug Labels table, however the latest drug label for Bidil available (updated on 03/27/2013) does not specifically mention genetic or biomarker testing for these genes. The label does contain information relating to the metabolism of hydralazine by acetylation. NAT1 and NAT2 are acetyltransferase enzymes. The label states that individuals who are 'fast acetylators' may have reduced exposure to hydralazine and those that are 'slow acetylators' may have higher bioavailability, although the clinical consequence of this is not mentioned. Acetylation status of an individual can be determined by examining genetic variants in the NAT2 gene (see NAT2 VIP summary).

Excerpt from the Hydralazine hydrochloride and isosorbide dinitrate (Bidil) drug label in the Pharmacokinetics section:

Hydralazine is metabolized by acetylation, ring oxidation and conjugation with endogenous compounds including pyruvic acid. Acetylation occurs predominantly during the first-pass after oral administration which explains the dependence of the absolute bioavailability on the acetylator phenotype. About 50% of patients are fast acetylators and have lower exposure.


In patients with heart failure, mean absolute bioavailability of a single oral dose of hydralazine 75 mg varies from 10 to 26%, with the higher percentages in slow acetylators.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Isosorbide and Hydralazine (BiDil) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Eye Diseases
    • Precautions section
    • source: PHONT
  • Heart Failure
    • Indications & usage section, Adverse reactions section
    • source: PHONT
  • Ischemia
    • Precautions section
    • source: PHONT

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all variant annotations for isosorbide dinitrate

Gene ? Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA
rs5443 NC_000012.11:g.6954875C>T, NC_000012.12:g.6845711C>T, NG_009100.1:g.10501C>T, NM_001297571.1:c.822C>T, NM_002075.3:c.825C>T, NP_001284500.1:p.Ser274=, NP_002066.1:p.Ser275=, NW_003871083.2:g.47295C>T, XM_005253679.1:c.825C>T, XM_005253680.1:c.822C>T, XM_005253681.1:c.702-6C>T, XM_005277751.1:c.825C>T, XM_005277752.1:c.822C>T, XM_005277753.1:c.702-6C>T, XM_011520953.1:c.825C>T, XM_011520954.1:c.822C>T, XM_011521027.1:c.*1818G>A, XM_011521028.1:c.*1818G>A, XM_011521029.1:c.*2036G>A, XM_011521030.1:c.*1969G>A, XP_005253736.1:p.Ser275=, XP_005253737.1:p.Ser274=, XP_005277808.1:p.Ser275=, XP_005277809.1:p.Ser274=, XP_011519255.1:p.Ser275=, XP_011519256.1:p.Ser274=, rs2230334, rs3138516, rs57419337, rs6489738
C > T
SNP
S274S
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Generic Names
  • Dianhydrosorbitol 2,5-dinitrate
  • Sorbide nitrate
  • Sorbide, dinitrate
  • Sorbidnitrate
Trade Names
  • Cardio 10
  • Cardis
  • Carvanil
  • Carvasin
  • Cedocard
  • Claodical
  • Cornilat
  • Coronex
  • Corosorbide
  • Difutrat
  • Dilatrate
  • Dilatrate-SR
  • Dinitrosorbide
  • Emoper
  • Flindix
  • Harrical
  • IBD 20
  • ISD
  • ISDN
  • Ismotic
  • Iso-Bid
  • Isochron
  • Isoket
  • Isorbid
  • Isordil
  • Isordil Tembids
  • Isostat
  • Isotrate
  • Korodil
  • Lomilan
  • Maycor
  • Myorexon
  • Nitrosorbid
  • Nitrosorbide
  • Nitrosorbon
  • Nosim
  • Resoidan
  • Rifloc Retard
  • Rigedal
  • Sorbangil
  • Sorbide T.D.
  • Sorbidilat
  • Sorbislo
  • Sorbitrate
  • Sorbonit
  • Sorquad
  • Tinidil
  • Titradose
  • Vascardin
  • Vasodilat
  • Vasorbate
  • Xanyl
Brand Mixture Names
  • BiDil (isosorbide dinitrate + hydralazine hydrochloride)

PharmGKB Accession Id

PA450125

Type(s):

Drug

Description

A vasodilator used in the treatment of angina pectoris. Its actions are similar to nitroglycerin but with a slower onset of action.

Source: Drug Bank

Indication

For the prevention of angina pectoris due to coronary artery disease.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Similar to other nitrites and organic nitrates, isosorbide dinitrate is converted to nitric oxide (NO), an active intermediate compound which activates the enzyme guanylate cyclase (atrial natriuretic peptide receptor A). This stimulates the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP) which then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber. The subsequent release of calcium ions results in the relaxation of the smooth muscle cells and vasodilation.

Source: Drug Bank

Pharmacology

Isosorbide Dinitrate is a moderate to long acting oral organic nitrate used for the relief and prophylactic management of angina pectoris. It relaxes the vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end- diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure.

Source: Drug Bank

Food Interaction

Take without regard to meals. Absorption is faster on an empty stomach.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic

Source: Drug Bank

Protein Binding

Very low

Source: Drug Bank

Absorption

Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. The average bioavailability of isosorbide dinitrate is about 25%.

Source: Drug Bank

Half-Life

1 hour

Source: Drug Bank

Toxicity

Symptoms of overdose include reduced cardiac output and hypotension.

Source: Drug Bank

Volume of Distribution

  • 2 to 4 L/kg

Source: Drug Bank

Chemical Properties

Chemical Formula

C6H8N2O8

Source: Drug Bank

Isomeric SMILES

C1[C@H]([C@@H]2[C@H](O1)[C@H](CO2)O[N+](=O)[O-])O[N+](=O)[O-]

Source: Drug Bank

[H][C@]12OC[C@H](O[N+]([O-])=O)[C@@]1([H])OC[C@H]2O[N+]([O-])=O

Source: Drug Bank

Canonical SMILES

[O-][N+]

Source: Drug Bank

Average Molecular Weight

236.1363

Source: Drug Bank

Monoisotopic Molecular Weight

236.028065242

Source: Drug Bank

SMILES

[H][C@]12OC[C@H](O[N+]([O-])=O)[C@@]1([H])OC[C@H]2O[N+]([O-])=O

Source: Drug Bank

InChI String

InChI=1S/C6H8N2O8/c9-7(10)15-3-1-13-6-4(16-8(11)12)2-14-5(3)6/h3-6H,1-2H2/t3-,4+,5-,6-/m1/s1

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CORIN
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
G6PD
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
GNB3
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
NAT2
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
NPPB

Drug Targets

Gene Description
NPR1 (source: Drug Bank)

Drug Interactions

Interaction Description
isosorbide dinitrate - dihydroergotamine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - dihydroergotoxine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - ergonovine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - ergonovine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - ergotamine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - methylergonovine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - methylergonovine Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - methysergide Possible antagonism of action (source: Drug Bank)
isosorbide dinitrate - sildenafil Possible significant hypotension with this combination (source: Drug Bank)
isosorbide dinitrate - sildenafil Possible significant hypotension with this combination (source: Drug Bank)
isosorbide dinitrate - tadalafil Possible significant hypotension with this combination (source: Drug Bank)
isosorbide dinitrate - tadalafil Possible significant hypotension with this combination (source: Drug Bank)
isosorbide dinitrate - vardenafil Possible significant hypotension with this combination (source: Drug Bank)
isosorbide dinitrate - vardenafil Possible significant hypotension with this combination (source: Drug Bank)

Curated Information ?

Publications related to isosorbide dinitrate: 5

No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT. JACC. Heart failure. 2014. McNamara Dennis M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug safety : an international journal of medical toxicology and drug experience. 2010. Youngster Ilan, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Ocular hemodynamic effects of nitrovasodilators in healthy subjects. Clinical pharmacology and therapeutics. 2010. Schmidl D, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy. Circulation. Heart failure. 2009. Rame J Eduardo, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. The New England journal of medicine. 2004. Taylor Anne L, et al. PubMed

LinkOuts

National Drug Code Directory:
0008-4139-01
DrugBank:
DB00883
ChEBI:
6061
KEGG Compound:
C07456
KEGG Drug:
D00516
PubChem Compound:
6883
PubChem Substance:
46506412
7979661
Drugs Product Database (DPD):
670944
ChemSpider:
6619
Therapeutic Targets Database:
DAP001057

Clinical Trials

These are trials that mention isosorbide dinitrate and are related to either pharmacogenetics or pharmacogenomics.

No trials found.

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Sources for PharmGKB drug information: DrugBank, PubChem.