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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:
other information
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:
Plasma Concentrations and Pharmacokinetics of Dimethylsulfoxide and Its Metabolites in Patients Undergoing Peripheral-Blond Stem-Cell Transplants
Author:
Egorin MJ, Rosen M, Sridhara R, Sensenbrenner L and Cottler-Fox M
Year:
1998
Bibliographic source:
J Clin Oncol, 16(2), 610-615

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Test compound Dimethylsulfoxyde
CAS no.: 67-68-5
Source: Research Industris, Salt Lake City, Utah
Batch : no data
Purity : no data
Radiolabelling:
no

Test animals

Species:
human
Sex:
not specified

Administration / exposure

Route of administration:
intravenous
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
Infusions lasted between 20 and 120 minutes.
Doses / concentrations
Remarks:
Doses / Concentrations:
18 to 58.5 ml (equivalent to 254 to 824 mmol) DMSO
No. of animals per sex per dose:
Ten patients who underwent autologous stem-cell transplant preserved with DMSO for a variety of solid tumors or lymphoma (5 carcinomas of the breast. one ovarian carcinoma, one testicular carcinoma, and three non-Hodgkin's lymphotnas) participated in this study.
Details on dosing and sampling:
Blood was sampled at multiple times after the stem-cell infusion. Urine was pooled during the 24 hours post-infusion. DMSO, DMSO2, and DMS were assayed simultaneously by gas chromatography. A one-compartment model with saturable elimination proved most suitable for fitting plasma DMSO concentration versus time data.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
DMSO2 was detectable in plasma by 5 minutes after the end of infusion (Figure 2) and its concentrations increased in plasma during the first 24 hours after completion of DMSO delivery. Peak plasma DMSO concentrations were 19.1 ± 6.3mmol/L. Between 24 and 48 hours (the last time at which blood was sampled), plasma concentrations of DMSO2 mained stable at 4.5 to 5 mmol/L. DMS was readily detectable in plasma by 5 minutes after completion of DMSO delivery (Figure 2), and plasma concentrations of this DMSO metabolite remained essentially constant at 3 to 5 mmol/L troughout the 48 hours during which blood was sampled.
Details on excretion:
Urinary excretion of DMSO and DMSO2 accounted for 44% ± 4% and 4% ± 1%, respectively, of the administered DMSO dose. Renal clearance of DMSO was 14.1± 3.4 ml/min
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: Vc (DMSO) = 37.3 +/- 17.0 L
Toxicokinetic parameters:
other: Vmax (DMSO) = 0.99=/- 0.57 mmol/h
Toxicokinetic parameters:
other: Km (DMSO) = 5.2 +/- 5.0 mmol/L

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Dimethyl sulfone (DMSO2) and dimethyl sulfide (DMS)

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
In human patients undergoing an autologous stem-cell transplant preserved with DMSO, plasma concentrations of DMSO and its metabolites (DMS and DMSO2) remained essentially constant at 3 to 5 mmol/L troughout the 48 hours during which blood was sampled.