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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets scientific standards with acceptable restrictions (no details about the test substance).

Data source

Reference
Reference Type:
publication
Title:
Clinical pharmacology of oral and iv N-methylformamide: a pharmacologic basis for lack of clinical antineoplastic activity
Author:
Rowinskv EK, Noe DA, Orr DW, Louise B. Grochow LB, Ettinger D, Donehower RC
Year:
1988
Bibliographic source:
J Natl Cancer Inst 80: 671-678

Materials and methods

Objective of study:
absorption
Principles of method if other than guideline:
Absorption in humans was measured via plasma levels after ingestion
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
N-methylformamide
EC Number:
204-624-6
EC Name:
N-methylformamide
Cas Number:
123-39-7
Molecular formula:
C2H5NO
IUPAC Name:
N-methylformamide
Details on test material:
no details
Radiolabelling:
no

Test animals

Species:
human
Sex:
not specified
Details on test animals or test system and environmental conditions:
patients were treated in the phase 1 study

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
physiological saline
Details on exposure:
N-methylformamide (NMF) was mixed with 100 mL of orange juice and ingested at approximately 9 A.M.
Duration and frequency of treatment / exposure:
data on absorption taken from single application
Doses / concentrations
Remarks:
Doses / Concentrations:
see Table below
No. of animals per sex per dose / concentration:
Totally 22 patients
Control animals:
no
Positive control reference chemical:
no
Details on study design:
Reexamination of the toxicity and pharmacology (side effects in Section 7.10.3).
Details on dosing and sampling:
NMF was administered at doses of 400, 500, 600, and 700 mg/m² on Mondays, Wednesdays, and Fridays X 4 weeks every 6 weeks.
Blood samples were obtained before the first day of NMF and at 5, 10, 20, 30, 60, and 90 min and 2, 3, 4, 6, and 24 h following drug ingestion; samples were collected prior to and 1 and 24 hr after the second and third doses (Wednesday and Friday).
Statistics:
Mann-Whitney U test for unpaired data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The gastrointestinal absorption of NMF was rapid, the average absorption haif-life was 7.2 min.
Nearly complete gastrointestinal absorption: the bioavailability (F) of oral NMF was 0.87 (as the ratio of the constants of proportionality between AUC and dose for the oral and iv dosing).

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No metabolites were identified.

Any other information on results incl. tables

Absorption parameters in humans after ingestion of N-methylformamide

Means +- standard error

Dose
in mg/m²

Cmax
(mmol/l)

Tmax
(min)

Absorption constant Ka

AUC
(min x mmol/l)

400 (n=6)

0.33+-0.03

75.5+-19.6

0.0646

301+-68

500 (n=7)

0.46+-0.05

72.8+-15.3

0.1310

332+-60

600 (n=6)

0.46+-0.06

74.0+-12.1

0.0602

322+-62

700 (n=3)

0.68+-0.08

69.3+-22.1

0.0782

666+-31

Applicant's summary and conclusion

Conclusions:
The gastrointestinal absorption of the test substance in humans after ingestion was rapid and nearly complete.
Executive summary:

Meets scientific standards with acceptable restrictions (no details about the test substance).

In this pharmacokinetic study patients ingested the N-methylformamide (NMF) mixed with fruit juice. The test substance was administered to groups of 3 -7 patients at doses of 400, 500, 600, and 700 mg/m². Blood samples were obtained before the first day of NMF and at 5, 10, 20, 30, 60, and 90 min and 2, 3, 4, 6, and 24 h following drug ingestion. Peak concentrations of NMF in plasma (0.33 -0.68 mmol/l, dose dependent) were reached appr. 70 minutes after ingestion. The average absorption haif-life was 7.2 min. The bioavailability (F) of oral NMF was 0.87.

Conclusion: The gastrointestinal absorption of the test substance in humans after ingestion was rapid and nearly complete.

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