Phenothiazine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Article published in peer-reviewed journal. Study not according to GLP or OECD guidelines. However, materials and methods as well as results and discussion are sufficiently described.

Data source

Reference

Reference Type:

publication

Title:

Fate of the anthelmintic, phenothiazine, in man

Author:

Mitchell, S.C. et al.

Year:

2002

Bibliographic source:

Xenobiotica (2002), Vol. 32, No. 9, 771-782

Materials and methods

Objective of study:

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

- Radio labelled Phenothiazine has been administered orally to two healthy adult male volunteers
- Faeces and urine were collected
- Study lasted 5 days

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Phenothiazine

EC Number:

202-196-5

EC Name:

Phenothiazine

Cas Number:

92-84-2

Molecular formula:

C12H9NS

IUPAC Name:

10H-phenothiazine

Details on test material:

Phenothiazine
- Phenothiazine (Sigma-Aldrich Ltd (Dorset, UK) was purified by recrystallisation from diethyl ether then aqueous ethanol to give light tan crystals
- Melting Point: 181 - 183 °C
- UV absorption: peaks at 254 and 317nm
- Mass spectrum: m/z 199

Radiolabelled Phenothiazine
- Radiolabelled Phenothiazine was synthesised by refluxing elementary [35 S]-sulphur (Nycomed-Amersham, UK) with diphenylamine in a molar ratio of 2:1.3 for 1hr at 180°C in 1,2-dichlorobenzene under an atmosphere of nitrogen; 1% (w/w) iodine was added as catalyst
- Radioactive Phenothiazine also was purified by recrystallisation to give yellow crystals
- Specific activity: 189.4mCi/mol
- Radiochemical purity: >98% (TLC)
- Mixed melting point: 181 - 183 °C

Radiolabelling:

yes

Remarks:

[35 S]-phenothiazine

Test animals

Species:

human

Strain:

not specified

Sex:

male

Administration / exposure

Route of administration:

oral: capsule

Vehicle:

other: gelatin capsule was given with water

Duration and frequency of treatment / exposure:

- Administration 2hrs after light breakfast single exposure
- Study period: 5 days

Doses / concentrations

Remarks:

Doses / Concentrations:
Single dose of 6mg/kg body weight

No. of animals per sex per dose / concentration:

2 male volunteers

Control animals:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

see below

Main ADME results 2

Type:

metabolism

Results:

see below

Toxicokinetic / pharmacokinetic studies

Details on excretion:

- Similar results for both volunteers
- 1/3 of the administered radioactivity was recovered from the urine, with the majority being voided during the first day
- 2/3 of the radioactive dose was recovered from faeces over 3-4 days with excretion tabering off towards the end of the study
- Overall, excellent recoveries of 98.4% and 100.4% were achieved

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

- Conjugates (phenothiazine N-glucorinide and leucophenothiazone sulphate)
- Thionol
- Phenothazine sulphoxide
- Phenothiazone

Any other information on results incl. tables

Urine

- More than 90% of recovered radioactivity was associated to the conjugates phenothiazine-N-glucuronide and leucophenothiazone sulphate, while less than 10% were accounted for the metabolites. The most abundant metabolite was phenothiazine sulphoxide

Faeces

- Only radioactive component found in extracts of faeces was assigned to the parent compound phenothiazine

- Methanolic extraction proved to be efficient in removing [³⁵S]-phenothiazine added to control faeces with recovery rates of about 80%; vice versa this means that a certain amount of radioactivity could not be accounted for

- It is assumed that the portions that could not be extracted were bound to cellulose and other polyphenolic components of the faeces

- Incubation of metabolites of phenothiazine with faeces resulted in no chemical alterations except for the nearly quantitative reduction of phenothiazine sulphoxide to phenothiazine

Half life

- Graphical plotting of the present 0 -24h urinary data was suggesting a biphasic excretion pattern with an initial half-life of around 6h (0 -12h) and a latter half-life of 16h (12 -24h period)

- Given half life is only to be considered as a rough estimate (was not focus of this study), because there are only few data points during this first day and there are only two volunteers.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Executive summary:

Radio labeled [35S]-phenothiazine has been administered orally to two healthy adult male volunteers. The administered dose was 6mg/kg body weight. About two thirds of the radioactivity were found to be excreted via faeces, the remainder via urine. Half-life (biphasic) was estimated to be 6 -16hrs. Radioactivity was completely recovered in the the course of the five day study.

Based on urine data is was shown that metabolism occurred via ring carbon oxidation to form phenothiazone and thionol and via ring sulphur oxidation to form phenothiazine sulphoxide. The vast majority of urinary material was present in the form of conjugates of phenothiazine and phenothiazone. Only unchanged phenothiazine was detected in faeces. Phenothiazine sulphoxide was reduced to phenothiazine during incubation with faecal homogenates.