Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: information from secondary source
Adequacy of study:
key study
Study period:
2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
A reliable secondary source, summarising ISDN pharmaco-toxicological properties, was used. However, the primary sources were not revisited in order to verify their contents; for this reason reliability score 2 was used. The used secondary source has been updated on January, 2011; therefore it covers the most updated literature on the substance.

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
No information
Bibliographic source:
Physicians' desk reference
Reference Type:
secondary source
Title:
No information
Year:
2011
Bibliographic source:
Drugdex Drug Evaluation: DRUGDEX® System. Thomson Reuters, Greenwood Village, Colorado.

Materials and methods

Objective of study:
other: assessment of pharmacokinetic parameters
Test guideline
Qualifier:
no guideline available
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: about 4 h for elimination
Test no.:
#2
Toxicokinetic parameters:
other: The distribution volume is 2-4 L/Kg
Test no.:
#3
Toxicokinetic parameters:
other: The clearance is 2-4 L/min

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
There are two metabolites: isosorbide-2-mononitrate (half life is about 2 hours) and isosorbide-5-mononitrate (half life is about 5 hours).

Any other information on results incl. tables

After oral administration of both single and repeated doses (15, 30, 60 and 120 mg four times daily) of ISDN, peak serum levels are observed after 0.5 to 1 hours. Oral bioavailability ranges from 22% to 59%; it may be affected by food (reduced absorption); multiple-dose studies of ingested ISDN have shown progressive increases in bioavailability during chronic administration.

Protein binding is minimal. In humans the volume of distribution ranges from 48 to 473 liters (2 -4 L/kg). ISDN is metabolized to isosorbide-5-mononitrate and to isosorbide-2-mononitrate. The excretion is mainly renal (80% to 90% of the administered dose): the majority is excreted as conjugated metabolites within 24 hours . Total body clearance is 2 -4 liters/minute. During chronic administration, clearance decreased with increasing dose. The elimination half-life after oral administration is 4 hours.

The daily dose-free interval is at least 14 hours due to the half-lives of ISDN and its active metabolites.

Applicant's summary and conclusion

Executive summary:

After oral administration of both single and repeated doses (15, 30, 60 and 120 mg four times daily) of ISDN, peak serum levels are observed after 0.5 to 1 hours. Oral bioavailability ranges from 22% to 59%; it may be affected by food (reduced absorption); multiple-dose studies of ingested ISDN have shown progressive increases in bioavailability during chronic administration.

Protein binding is minimal. In humans the volume of distribution ranges from 48 to 473 liters (2 -4 L/kg). ISDN is metabolized to isosorbide-5-mononitrate and to isosorbide-2-mononitrate. The excretion is mainly renal (80% to 90% of the administered dose): the majority is excreted as conjugated metabolites within 24 hours . Total body clearance is 2 -4 liters/minute. During chronic administration, clearance decreased with increasing dose. The elimination half-life after oral administration is 4 hours.

The daily dose-free interval is at least 14 hours due to the half-lives of ISDN and its active metabolites.