(3E)-3-[[4-(2-carboxyethylcarbamoyl)phenyl]hydrazinylidene]-6-oxocyclohexa-1,4-diene-1-carboxylic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

2000

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test:
- Short description of test conditions: radiolabelled Basalazide sodium (BSZ) was administered to rats as a single i.v. dose at 120 mg/kg
- Parameters analysed / observed: Blood, urine and Faeces was sampled and levels of BSZ and its metabolites were determined. Tissue samples from a variety of organs were collected for distribution study. Radioactivity was determined via LSC.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Benzoic acid, 5-[(1E)-[4-[[(2-carboxyethyl)amino]carbonyl]phenyl]azo]-2- hydroxy-, disodium salt, dihydrate

Cas Number:

150399-21-6

Molecular formula:

C17H13N3O6Na2 . 2H2O

IUPAC Name:

Benzoic acid, 5-[(1E)-[4-[[(2-carboxyethyl)amino]carbonyl]phenyl]azo]-2- hydroxy-, disodium salt, dihydrate

Test material form:

solid

Specific details on test material used for the study:

The study was performed on balsalazide disodium, but it will reach a common moiety in the blood after oral dosing , whether BSZ or BSA.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

120 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose / concentration:

Not stated

Control animals:

no

Positive control reference chemical:

Not stated

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood
- Time and frequency of sampling: 1,3,6,9,12,18 and 24 hours after dosing

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, tissues,
- Time and frequency of sampling: 1,3,6,9,12,18 and 24 hours after dosing
- Method type(s) for identification HPLC-UV, Liquid scintillation counting

Statistics:

None specified

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Oral bioavailability was very low (0.52-0.62%)

Main ADME results 2

Type:

distribution

Results:

Missing page in review document. No distribution information available

Main ADME results 3

Type:

metabolism

Results:

Four metabolites were formed. 5-amino salicylic acid (ASA) which is N-acetylated to N-acetyl-5-amino-salicylic acid (NASA). 4 aminobenzoyl-5-alanine (ABA) which is N-acetylated to N-acetyl-4-aminobenzoyl-5-alanine (NABA).

Main ADME results 4

Type:

excretion

Results:

Following a single oral dose, 4-ABA (one of the metabolites) was found in large quantities in Faeces and in small amounts in plasma. The majority of the applied radioactivity (approx 92%) was found in the faeces and a small (approx 5-8%) in the urine.

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

No information available.

Details on excretion:

Following a single oral dose, 4-ABA (one of the metabolites) was found in large quantities in Faeces and in small amounts in plasma. The majority of the applied radioactivity (approx 92%) was found in the faeces and a small (approx 5-8%) in the urine for both dose levels. In the urine, low amounts of basalazide acid (sodium salt) was recovered with the major metabolite being NABA.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Four metabolites were reported. These were assigned as:
1) 5-aminosalicylic acid (ASA)
2) N- acetyl-5-amino-salicylic acid (NASA, derived by N-acetylation of ASA)
3) 4-aminobenzoyl-5-alanine (ABA)
4) N-acetyl-4-aminobenzoyl-5-alanine (NABA, derived by N-acetylation of ABA)

Any other information on results incl. tables

Single dose of Balsalazide to rat

Compound	Dose of Balsalazide (mmol/kg)	Route/group	Cmax (nmol/ml)	Tmax (h)	AUC (nmol.h/ml)	Urine (nmole/24h)	Clr (ml/min)
Radioactivity	0.274	Oral (A)	3.574	9.00	40.72	NA	NA
Radioactivity	4.573	Oral(B)	26.78	12.00	373.8	NA	NA
Radioactivity	0.274	IV	NA	NA	269.0	NA	NA
Balsalazide	0.274	Oral (A)	1.091	1.00	3.072	273.5	1.484
Balsalazide	4.573	Oral(B)	8.505	1.00	42.56	3470	1.359
Balsalazide	0.274	IV	NA	NA	491.9	18452	0.625
NABA	0.274	Oral (A)	1.838	9.00	15.73	1897	2.009
NABA	4.573	Oral(B)	10.71	12.00	137.0	10382	1.263
NABA	0.274	IV	NA	NA	ID	1303	ID
NASA	0.274	Oral (A)	7.585	9.00	50.75	6867	2.255
NASA	4.573	Oral(B)	51.28	9.00	622.0	75690	2.028
NASA	0.274	IV	NA	NA	29.16	5580	3.189
ABA	0.274	Oral (A)	0.310	9.00	ID	ID	ID
ABA	4.573	Oral(B)	3.974	12.00	34.20	6238	3.040
ABA	0.274	IV	ID	ID	ID	ID	ID
ASA	0.274	Oral (A)	1.946	9.00	ID	ID	ID
ASA	4.573	Oral(B)	73.05	12.00	522.2	17700	0.565
ASA	0.274	IV	NA	NA	ID	ID	ID

ID = Insufficient data to derive parameter

NA = not applicable

Applicant's summary and conclusion

Conclusions:

The results of the i.v. dosing are quite different to the oral dosing. After dosing, radioactivity in the plasma declines much faster than the same dose via the oral route. Excretion of a high (38% dose) percentage as intact balsalazide via urine is quite interesting as the in vitro plasma protein binding was determined to be 96-99% and protein bound molecules cannot be filtered through the kidney into urine. Clearly, in vivo the parent molecule can be excreted despite high plasma protein binding suggesting that either the plasma protein binding in vivo is much lower than in vitro indicates, or there is reversal of the binding within the kidneys.