Ethyl methyl sulphide

Basic toxicokinetics

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: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

The effects of a synthetic diet on the pharmacokinetics of ethyl methyl sulphide and its sulphoxide and sulphone metabolites in rats

Author:

Nnane IP, Damani LA and Hutt AJ

Year:

2001

Bibliographic source:

European Journal of Drug Metabolism and Pharmacokinetics, 26(1/2), 17-24

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

- characterization of the pharmacokinetics of EMS at different doses following intravenous and oral administration,
- evaluation of modifications of the pharmacokinetics of EMS generated by placing male wistar rats on chemically defined diets?
- evaluation of metabolite pharmacoklnetics in control rats and rats maintained on the synthetic diet after administration of EMS or the S-oxygenated metabolites metabolites.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl methyl sulphide

EC Number:

210-868-4

EC Name:

Ethyl methyl sulphide

Cas Number:

624-89-5

Molecular formula:

C3H8S

IUPAC Name:

(methylsulfanyl)ethane

Test material form:

other: liquid

Details on test material:

EMS was purchased from Aldrich chemical company (Gillingham, Dorset, UK). EMSO and EMS02 were synthesized by the laboratory using published procedures for oxidation of sulphides. The chemical purity of all compounds was greater than 98%.

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Bantin and Kingman Limited (Aldbrough, Hull, U.K.)
- Age at study initiation: no data
- Weight at study initiation: 230-280g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes/no
- Diet: normal rat chow or synthetic diet [47% dextrln (type 2), 23% sucrose, 10% corn oil, 14% amino acids and supplemented with vitamins and minerals], ad libitum
- Water (e.g. ad libitum): no data
- Acclimation period: at least 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 50
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

other: oral and iv.

Vehicle:

not specified

Duration and frequency of treatment / exposure:

Single administration

Doses / concentrations

Remarks:

Doses / Concentrations:
EMS: 40 mg/kg (orally); 10, 20 and 40 mg/kg (intravenously)
EMSO: 5 mg/kg (intravenously)
EMSO2: 15 mg/kg (intravenously)

No. of animals per sex per dose / concentration:

6

Control animals:

no

Details on study design:

The rats (n = 6) were surgically prepared under hypnorm/hypnovel anaesthesia by implanting indwelling cannula into the jugular veln and the carotid
artery, 24 h prior to drug administration and blood sampllng. EMS, EMSO or EMS02 were admlnistered as a single bolus dose through the jugular veln or orally by gavage.

Details on dosing and sampling:

Arterial blood samples (250 ml ??) were collected in heparinized tubes pre-dose and post-dose at 5, 15, 30, 45 mins, and at 1,2, 3,4,5, 6, 7, 8 and24 h.

Blood Jevels of EMS were analysed by a sensitive headspace gas chromatographic assay. The collected blood (250 ml) was placed in 5 ml serum bottles. The internal standard, dimethyl sulphide (25 ml of 2S mg/ml), was added and this was followed by addition of potassium carbonate (0.1 g). The stoppered vials were then vortex mixed and heated at 80°C for 20- 30 mins in a water bath. An aliquot (5 ml) of the headspace generated was injected directly onto the GLC column (2 m x 0.4 cm, 4% Carbowax 20M/0.8% w/w KOH on Carbopack B).
Blood levels of the sulphoxide and sulphone were monitored by a separate gas chromatography assay. To blood samples already analysed by headspace GLC, Sodium hydroxide (50 µl, 0.1 M), the internai standard, n-propyl sul phone (10 µl,4 mg/ml), and sodium chloride (0.1 g) were added. Samples were then extracted with dichloromethane (2 x S ml). The pooled extracts were evaporated to dryness and reconstituted in 20 µl of methanol. Aliqutos (5µl) of the reconstituted extracts were injected onto the GLC column (10% Carbowax 20 M on Chromosorb W (HP), 2 m x 0.4 cm).

Statistics:

Model independent pharmacokinetic parameters were calculated with the computer program Toplit veniion 1.0 using the standard non-compartmental equations.

One way analysis of variance ( ANOV A) was used to obtain probabllity values (p) and compare different treatment groups. A p value of less than 0.05 was considered statistically significant.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

EMS (20 mg/kg, iv) was rapidly eliminated from rat blood with a terminal half-life of 0.14 h and was not detectable 1 h after administration. EMSO was detected in rat blood between 0.083 and 5 h. The blood levels of EMSO peaked at about 1 h and then declined with a slope that was shallower than that of the parent EMS. The appearance of detectable blood levels of EMSO2 was delayed to about 0.5 h after intravenous administration of EMS. The blood levels of EMSO2 then increased reaching a peak between 6 and 7 hours after administration of EMS and persisted in the systemic circulation 24 h post-dose.
The pharmacokinetics of EMS was linear over the dose range investigated.
The absorption of EMS after oral administration was rapid and the oral bioavailability was extensive (75%). After oral administration of EMS (40 mg/kg) the maximum blood concentration (Cmax.) was attained within the first 0.083 h of blood sampling and then dec1ined monoexponentially.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Ethylmethylsulphoxide (EMSO)
Ethylmethylsulphone (EMSO2)

Applicant's summary and conclusion

Executive summary:

Ethyl methyl sulphide (EMS), a simple dialkyl sulphide, is oxidized to the corresponding sulphoxide (EMSO) and sulphone (EMS02) derivatives both in vitro and in vivo. Two distinct enzymatic pathways appear to be involved in this sulphoxidation process; the flavin-containing monooxygenasen (FMO) is largely responsib1e for the S-oxidation of EMS to its sulphoxide while both cytochrome P-450 and FMO are involved in the further oxidation of the sulphoxide to the sulphone. The pharmacokinetics of EMS and its sulphoxide and sulphone metabolites were examined in male Wistar rats placed on normal rat chow and those placed on a synthetic diet. Blood levels of EMS were analysed by a sensitive headspace gas chromatography assay. A separate gas chromatography assay was developed to monitor the blood levels of EMSO and EMSO2.. The pharmacokinetics of EMS in control rats were linear from 10 to 40 mg/kg dose range. The blood concentration-time profile of EMS declined monoexponentially, EMS was rapidly eliminated from rat blood with a terminal half-life of 0.14h and was not detectable 1 h after administration. Following intravenous administration of EMSO (5 mg/kg), the blood concentration-time profile of EMSO declined with a terminal half -live (t1/2) of 1.46 h, about ten times longer than that of the parent sulphide. After administration of EMSO2 (15 mg/kg), the sulphone was metabolically stable and was eliminated very slowly from the blood. The in vivo disposition of EMS and EMSO were clearly altered in rats maintained on a synthetic diet following administration of EMS or EMSO. The pharmacokinetic data were consistent with a diminished drug oxidising capacity in rats placed on the synthetic diet and could serve as a useful probe for monitoring the regulation of FMO in animals.