Quinidine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The database does not provide additional information on the method.

Data source

Reference

Reference Type:

other: Database

Title:

HSDB - Hazardous Substances Data Bank

Author:

U.S. Department of Health & Human Services

Year:

2013

Bibliographic source:

http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Report date:

2013

Materials and methods

Principles of method if other than guideline:

There are no details on the method available.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Quinidine

EC Number:

200-279-0

EC Name:

Quinidine

Cas Number:

56-54-2

Molecular formula:

C20H24N2O2

IUPAC Name:

6'-methoxycinchonan-9-ol, 6'-methoxy-,(9S)-

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): Quinidine

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

70 to 80%

Main ADME results 2

Type:

distribution

Results:

70 to 80% of the drug is bound to plasma protein

Main ADME results 3

Type:

metabolism

Results:

50 to 90% of a dose of quinidine is metabolized in the liver

Main ADME results 4

Type:

excretion

Results:

50% of a dose of quinidine is excreted in urine

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Quinidine is almost completely absorbed from the gastrointestinal tract. However, because of hepatic first-pass effect, the absolute bioavailability is about 70 to 80% of the ingested dose.

Details on distribution in tissues:

About 70 to 80% of the drug is bound to plasma protein. The quinidine concentrations in liver are 10 to 30 times higher than those in plasma. Skeletal and cardiac muscle, brain and other tissues contain intermediate amounts. The red cell plasma partition ratio is 0.82.

Details on excretion:

The amount excreted unchanged in urine is variable but is about 17% of an administered dose. Up to 50% of a dose of quinidine (unchanged + metabolites) is excreted in urine within 24 hours after administration. 50 to 90% of a dose of quinidine is metabolized in the liver. Approximately 1 to 3% is excreted in the feces via the bile. Quinidine is excreted in breast milk.

Toxicokinetic parameters

Toxicokinetic parameters:

half-life 1st: 6-7 h

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

50 to 90% of quinidine is metabolized in the liver to hydroxylated products. Metabolites include 3-hydroxyquinidine, 2 oxoquinidinone, 0-desmethylquinidine, quinidine-N-oxide. The principal metabolite is 3 hydroxyquinidine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study resultsQuinidine is almost completely absorbed from the gastrointestinal tract. About 70 to 80% of the drug is bound to plasma protein. 50 to 90% of quinidine is metabolized in the liver to hydroxylated products. Up to 50% of a dose of quinidine is excreted in urine within 24 hours after administration. Approximately 1 to 3% is excreted in the feces via the bile. The half-life of quinidine is about 6 to 7 hours.

Executive summary:

According to the peer-reviewed database, HSDB, oral absorption of quinidine is the most frequent cause of intoxication. Quinidine is almost completely absorbed from the gastrointestinal tract. However, because of hepatic first-pass effect, the absolute bioavailability is about 70 to 80% of the ingested dose and may vary between patients and preparations. The time to plasma peak concentration is 1 to 3 hours for quinidine sulphate, 3 to 6 hours for quinidine gluconate and about 6 hours for quinidine polygalacturonate. Sustained-release quinidine is absorbed continuously over 8 to 12 hours. Absorption of quinidine after intramuscular injection may be erratic and unpredictable with incomplete absorption of the administered dose, probably due to precipitation of drug at the site of injection. About 70 to 80% of the drug is bound to plasma protein. Plasma protein binding is decreased in patients with chronic liver disease. The quinidine concentrations in liver are 10 to 30 times higher than those in plasma. Skeletal and cardiac muscle, brain and other tissues contain intermediate amounts. The red cell plasma partition ratio is 0.82. The half-life is about 6 to 7 hours. It is increased in chronic liver disease and in the elderly. It does not appear to be altered in congestive heart failure or renal failure. 50 to 90% of quinidine is metabolized in the liver to hydroxylated products. Metabolites include 3-hydroxyquinidine, 2 oxoquinidinone, 0-desmethylquinidine, quinidine-N-oxide. The principal metabolite is 3 hydroxyquinidine which exerts similar effects to quinidine and may account for part of the observed antiarrhythmic effects. The elimination kinetics of hydroxyquinidine appear to be similar to those of quinidine. The amount excreted unchanged in urine is variable but is about 17% of an administered dose. Up to 50% of a dose of quinidine (unchanged + metabolites) is excreted in urine within 24 hours after administration. Renal excretion is dependent upon the pH of the urine. 50 to 90% of a dose of quinidine is metabolized in the liver. Approximately 1 to 3% is excreted in the feces via the bile. Quinidine is excreted in breast milk.