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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 / concentrationsopen allclose all
Dose / conc.:
120 mg/kg bw/day (actual dose received)
Dose / conc.:
2 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Not stated
Control animals:
no
Positive control:
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 resultsopen allclose all
Type:
absorption
Results:
Oral bioavailability was very low (0.52-0.62%)
Type:
distribution
Results:
Missing page in review document. No distribution information available
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).
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.