N,N'-diacetylhydrazine

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: - Study well documented, meets generally accepted scientific principles, acceptable for assessment - non-GLP

Data source

Reference

Reference Type:

publication

Title:

Pharmacokinetics of isoniazid metabolism in man.

Author:

Ellard GA & Gammon PT

Year:

1976

Bibliographic source:

J Pharmacokinet Biopharm. 1976 Apr;4(2):83-113.

Materials and methods

Type of study / information:

in vivo investigation of adsorption, distribution, metabolism and excretion in man

Endpoint addressed:

basic toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- study I:
• two volunteers, one a slow acetylator the second a rapid acetylator took (bw: 63 and 62 kg respectively), on successive occasions separated by at least a week, oral doses of 10, 50, and 250 mg isoniazid, 50 and 500 mg acetylisoniazid, 10 mg isoniazid plus 50mg acetylisoniazid, 25mg isonicotinic acid, 116 mg diacetylhydrazine, 74mg monoacetylhydrazine (as 190 mg monoacetylhydraziniumfumarate), and 750 mg sulfadimidine, respectively.
• urine collection up to 48 h
• blood sampling of the slow acetylator after ingestion of the highest doses of isoniazid, acetylisoniazid, and isonicotinic acid
- study II:
• oral doses of 20 mg isoniazid/kg taken by 17 subjects
• blood sampling at 3 and 6 h post dosing
• urine sampling at 0-2.5, 2.5-3.5, 3.5-5.5, and 5.5-6.5 h post dosing
- study III:
• 13 volunteers, dosed with 600 mg isoniazid in a matrix formulation
• urine collection up to 48 h post dosing
• 25 tuberculosis patients, oral doses of 300 mg isoniazid plus 150 mg thiacetazone on 2 consecutive days
• 24 h urine
- Determination of concentrations of parent substance and metabolites by spectrometric methods (colorimetry and fluorometry)

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N'-diacetylhydrazine

EC Number:

221-576-1

EC Name:

N,N'-diacetylhydrazine

Cas Number:

3148-73-0

Molecular formula:

C4H8N2O2

IUPAC Name:

N'-acetylacetohydrazide

Details on test material:

- Name of test material (as cited in study report): diacetylhydrazine
- Physical state: not reported
- Analytical purity: not reported, but synthesis method cited: G. A. Ellard, P. T. Gammon, and S. M. Wallace. The determination of isoniazid and its metabolites acetylisoniazid, monoacetylhydrazine, diacetylhydrazine, isonicotinic acid and isonicotinylglycine in serum and urine. Biochem. J. 126:449-458 (1972).
- Impurities (identity and concentrations): not reported
- Stability under test conditions: not reported
- Storage condition of test material: not reported

Method

Ethical approval:

not specified

Details on study design:

Route of administration
- oral (unspecified), in water as vehicle

Duration and frequence of treatment
- study I: single oral exposure
- study II: single oral exposure
- study II:
• healthy volunteers: single oral exposure
• tuberculosis patients: oral doses at 2 consecutive days

Doses
- study I: 116 mg diacetylhydrazine (volunteers: 63 and 62 kg body weight)
- study II: 20 mg isoniazid/kg bw
- study II:
• healthy volunteers: 600 mg isoniazid per person
• tuberculosis patients: 300 mg isoniazid plus 150 mg thiacetazone per person

No. of participants
- study I: 2, 1 slow acetylator, 1 rapid acetylator
- study II: 17, 12 slow acetylators, 5 rapid acetylators
- study II:
• healthy volunteers: 13, 6 slow acetylators, 7 rapid acetylators
• tuberculosis patients: 25 tuberculosis patients

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE:
defined applied doses via the oral route (see above)

Results and discussion

Results:

Details on absorption
The rapidity of the urinary excretion rate of diacetylhydrazine indicates that it was very rapidly absorbed and distributed throughout the body. Absorption of diacetylhydrazine compounds was effectively complete.

Details on distribution in tissues
The rapidityof the urinary excretion rate of diacetylhydrazine indicates that it was very rapidly absorbed and distributed throughout the body. Absorption of diacetylhydrazine compounds was effectively complete.

Details on excretion
- maximal rates of urinary excretion occurred within 1 hr post administration of diacetylhydrazine, afterwards exponential decrease of the urinary excretion
- half-life of about 5 hr in urine.
- Excreted amounts:
• slow acetylator: 77% of the dose (unchanged)
• rapid acetylator: 86 % of the dose (unchanged)
• rate constants for the excretion of diacetylhydrazine: of 0.10 1/h and 0.12 1/h respectively
- "Further studies in tuberculosis patients with chronic renal failure have confirmed the conclusion that the terminal metabolites of isoniazid are isonicotinylglycine and diacetylhydrazine and have indicated that their elimination by extrarenal routes is minimal (G. A. Ellard and P. Sever, unpublished work)."

Details on metabolites
No metabolites of diacetylhydrazine were found.

Any other information on results incl. tables

- Only results relevant for diacetylhydrazine are reported. Results for Isoniazid are reported where helpful for comparison.

- Table 1:

Compound administered	Dose (mg)	Acetylator	Fluid	Period after dose° (hr)	Elimination equation*	Half-life (1/h)
Diacetylhydrazine	116	Slow	Urine	1.5-30.0 (7)	1.02 - 0.058t	5.2 ± 0.3
	116	Rapid	Urine	1.5-30.0 (7)	1.08 - 0.061t	4.9 ± 0.5

*Equation relating the change with time (t) in hours of the logarithm10 of the concentration of the administered compound in the plasma its rate of elimination in the urine (percent dose excreted/hr).

 

- Table 2: Cumulative Urinary Excretion of lsoniazid and Diacetylhydrazine as percent administered dose.

Compound administered	Isoniazid			Diacetylhydrazine
Dose (mg):	250	250	900	116	116
Collection period (hr):	48	48	48	48	48
Acetylator status'	S	R	S	S	R
Compound recovered
Acid-labile isoniazid	34.0	16.5	39.9	-	-
Acetylisoniazid	28.5	40.7	28.5	-	-
Diacetylhydrazine	5.7	26.8	4.5	76.8	86.1
Total hydrazidesd	68.2	84.0	72.9	76.8	86.1

 

- Table 3: Apparent first-order rate constants calculated for the conversion and excretion of isoniazid and the excretion of diacetylhydrazine

Compound	Dose (mg)	Process	First-order rate constant (1/h)
			Slow acetylator	Rapid acetylator
Isoniazid	250	Acetylation	0.11	0.39
	900		0.09
	900	Excretion and hydrazone formation	0.085
	900	Hydrolysis to isonicotinic acid	0.02
Diacetylhydrazine	116	Excretion	0.10	0.12

Applicant's summary and conclusion

Conclusions:

Absorption, distribution, metabolism and excretion of isoniazid and its metabolites were tested in different experimental settings in humans. The single exposure was via the oral route with water as vehicle. In this entry only the results for diacetylhydrazine are regarded. Based on the development of urine levels diacetylhydrazine is absorbed to a high extent (> 77 %) in both volunteers after a dose of ca. 1.85 mg/kg bw. No metabolites of diacetyl hydrazine are detected. All hydrazines detected are identical to the parent diacetylhydrazine. The half-life is ca. 5 h both in the slow as well as in the rapid acetylator. Therefore bioccumulation is not to be expected in humans.
The study is considered to be relevant as it is well documented, meets generally accepted scientific principles and described the toxicokinetic of the test item in humans. The number of volunteers is limited. Nevertheless generall assumptions on the toxicokinetic behaviour of diacetylhydrazine can be deduced from this study.

Executive summary:

Absorption, distribution, metabolism and excretion of isoniazid and its metabolites were tested in different experimental settings in humans. The single exposure was via the oral route with water as vehicle. In this entry only the results for diacetylhydrazine are regarded. In study I two volunteers, one a slow acetylator the second a rapid acetylator (bw: 63 and 62 kg respectively), took on successive occasions separated by at least a week, oral doses of 10, 50, and 250 mg isoniazid, 50 and 500 mg acetylisoniazid, 10 mg isoniazid plus 50mg acetylisoniazid, 25mg isonicotinic acid, 116 mg diacetylhydrazine, 74 mg monoacetylhydrazine (as 190 mg monoacetylhydraziniumfumarate), and 750 mg sulfadimidine, respectively. Urine was collected up to 48 h post dosing, blood was sampled of the slow acetylator after ingestion of the highest doses of isoniazid, acetylisoniazid, and isonicotinic acid. In study oral doses of 20 mg isoniazid/kg were taken by 17 subjects, blood sampling occurred at 3 and 6 h post dosing and urine sampling at 0 -2.5, 2.5 -3.5, 3.5 -5.5, and 5.5 -6.5 h post dosing. In study III 13 volunteers were dosed with 600 mg isoniazid in a matrix formulation, urine collected up to 48 h post dosing. In addition 25 tuberculosis patients received oral doses of 300 mg isoniazid plus 150 mg thiacetazone on 2 consecutive days and urine was sampled up to 24 h post exposure.Concentrations of parent substance and metabolites were determined by spectrometric methods (colorimetry and fluorometry). Results of study II and III are not relevant for the toxicokinetic of diacetylhydrazine. Based on the measurement of urine levels diacetylhydrazine is absorbed to a high extent (> 77 %) in both volunteers after a dose of ca. 1.85 mg/kg bw. No metabolites of diacetylhydrazine are detected. all hydrazines detected are identical to the parent diacetylhydrazine. The half-life is ca. 5 h both in the slow as well as in the rapid acetylator. Therefore bioccumulation is not to be expected in humans.

The study is considered to be relevant as it is well documented, meets generally accepted scientific principles and described the toxicokinetic of the test item in humans. The number of volunteers is limited. Nevertheless generall assumptions on the toxicokinetic behaviour of diacetylhydrazine can be deduced from this study.