Codeine sulphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to a guideline study conducted on a read-across material.

Justification for type of information:

The toxicological profile of the test material would not be different than that of codeine and the data are interchangeable. Codeine toxicology data is used to support the registered substance’s products in regulatory submissions. The test material is the sulfate salt form of codeine, a naturally occurring phenanthrene alkaloid and opioid agonist with analgesic, antidiarrheal, and antitussive activity.

Data source

Reference

Reference Type:

publication

Title:

NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF CODEINE (CAS NO. 76-57-3) IN F344/N RATS AND B6C3Fl MICE (FEED STUDIES)

Author:

NATIONAL TOXICOLOGY PROGRAM

Year:

1996

Bibliographic source:

NIH Publication No. 96-3360

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test material toxicokinetics in F344 rats of both sexes were determined during a 2-year chronic toxicology study using dosed feed as the exposure route with a 12-hr light/dark cycle starting at 7:00 a.m. Rats were allowed to access to dosed feed formulations ad libitum with test material concentrations at 0, 400, 800, and 1 600 ppm. Blood samples were collected from individual rats on days 7, 21, and 90 at 2:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00 - 8:00 a.m. Plasma concentrations of test material and morphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total amount of free test material and morphine released after samples were treated with β-glucuronidase.

GLP compliance:

not specified

Test material

Test material information

1

Reference substance name:

Codeine

EC Number:

200-969-1

EC Name:

Codeine

Cas Number:

76-57-3

Molecular formula:

C18H21NO3

IUPAC Name:

Codeine

Radiolabelling:

yes

Remarks:

[I-’H] test material (specific activity, 20 Ci/mmol)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Doses / concentrations

Remarks:

0, 400, 800 and 1 600 ppm

Results and discussion

Any other information on results incl. tables

Plasma concentrations of unconjugated test material increased with the daily amount of test material consumed and fluctuated over the course of the study. The peak plasma concentrations of the test material occurred at 11:00 p.m. on day 7. Overall, plasma concentration profiles of unconjugated test material were similar in both sexes. ANOVA analysis indicated that test material plasma concentrations were dose dependent (p < 0.01). In most cases, female rats had higher plasma concentrations of the test material and its metabolites than males. Plasma concentrations of unconjugated codeine consistently decreased from day 7 to day 90 (ANOVA, p < 0.01),which may be related to the decrease of test material intake over the course of the study. However, because the intake on day 7 and day 21 were comparable, the reduction in plasma test material concentrations may also have resulted from enzyme induction.

AUC values increased with dose (F-test, p < 0.01) and varied considerably throughout the study. However, the calculated AUC values generally decreased as the study progressed, which indicated that the test material did not accumulate during the study.

Plasma concentrations of conjugated test material were also determined. Results indicated that most test material was present in plasma as the unconjugated form, and the concentrations of conjugated test material were very low. Plasma concentrations of total test material (unconjugated and conjugated) were generally higher in females than in males, but the difference was less consistent than for free codeine. As expected, the estimated AUC values of total test material were slightly higher than the AUC values of unconjugated test material and also increased with dose (F-test, p < 0.01).

The distribution of test material and test material-derived metabolites in plasma (mean ± SE, N = 360) based on data from day 7 to day 90 was as follows: Free test material (11.8 ± 0.47 %) and conjugated test material (1.42 ± 0.l6 %).

Plasma concentrations of test material and total test material steadily decreased from day 7 to 16 months and then rebounded at 24 months.

In most cases, female rats showed higher plasma concentrations of the test material and its metabolites than males.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test plasma concentrations of both the test material and morphine steadily decreased from day 7 to 16 months and then rebounded at 24 months. Results also indicated that plasma concentrations of both the test material and morphine correlated well with the amounts of test material added to the feed.
Bioavailability of the test material using the dosed feed route increased with dose, varying from 10 % to 25 %. Concentrations of conjugated test material were very low. The results suggested that demethylation of the test material in rats is the main metabolic pathway and was maintained over the course of the study.

Executive summary:

The test material toxicokinetics in F344 rats of both sexes were determined during a 2-year chronic toxicology study using dosed feed as the exposure route with a 12-hr light/dark cycle starting at 7:00 a.m. Rats were allowed to access to dosed feed formulations ad libitum with test material concentrations at 0, 400, 800, and 1 600 ppm. Blood samples were collected from individual rats on days 7, 21, and 90 at 2:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00 - 8:00 a.m. Plasma concentrations of test material and morphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total amount of free test material and morphine released after samples were treated with β-glucuronidase.

Results indicated that plasma concentrations of both the test material and morphine steadily decreased from day 7 to 16 months and then rebounded at 24 months. Results also indicated that plasma concentrations of both the test material and morphine correlated well with the amounts of test material added to the feed.

Bioavailability of the test material using the dosed feed route increased with dose, varying from 10 % to 25 %. Concentrations of conjugated test material were very low. The results suggested that demethylation of the test material in rats is the main metabolic pathway and was maintained over the course of the study.