Betamethasone

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979/1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline study, some restrictions in design and/or reporting but otherwise adequate for assessment of the betamethasone mother/fetus transfer.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1980

Materials and methods

Type of study / information:

The plasma concentrations of betamethasone in a maternal peripheral vein (mv) and in the umbilical vein (uv) were measured at delivery in eleven patients after the administration of betamethasone phosphate equivalent to 8 mg betamethasone. Betamethasone concentrations were measured in plasma using a specific and sensitive HPLC assay.
After equilibration across the placenta has occurred, the plasma concentration of betamethasone in the umbilical vein will be approximately 25 to 30% of the concomitant maternal level.

Principles of method if other than guideline:

Examination of the betamethasone concentration on blood of eleven women, aged 27 to 37 years with estimated gestational ages ranging from 31 to 38 weeks, were carried out, after obtaining informed consent from the mother, on samples drawn from a maternal peripheral vein at delivery, and from the umbilical vein of the clamped cord after delivery of the placenta. To all of the women, betamethasone had been prescribed for antenatal administration. Betamethasone was administered as its phosphate ester, equivalent to 8 mg of betamethasone free alcholol, in one or two doses.
The interval from the time of the last dose to the time of delivery varied from 56 to 800 min.
HPLC determination was perrormed with prednisolone as internal standard. The retention time of betamethasone was 6.1 min while prednisolone retention time was 10.3 min. Betamethasone phosphate is not extracted from the biological matrix during the assay procedure and therefore does not interfere with the chromatography of betamethasone.
The specificity of the HPLC assay was also examined by detection at 240 nm and 254 nm, using two ultraviolet detectors connected in series.
The ratio of the absorbance of the chromatographic peak with a retention time of 6.1 rain at 240 nm to that at 254 nm was calculated and compared to the ratio observed when an authentic standard of betamethasone was injected directly into the chromatograph.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Betamethasone phosphate

IUPAC Name:

Betamethasone phosphate

Constituent 2

Reference substance name:

Betamethasone

EC Number:

206-825-4

EC Name:

Betamethasone

Cas Number:

378-44-9

Molecular formula:

C22H29FO5

IUPAC Name:

9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione

Details on test material:

- Name of test material (as cited in study report): Betamethasone phosphate
- Molecular formula (if other than submission substance): C22H28FNa2O8P
- Molecular weight (if other than submission substance): 516.404624 [g/mol]
- Smiles notation (if other than submission substance): CC1CC2C3CCC4=CC(=O)C=CC4(C3(C(CC2(C1(C(=O)COP(=O)([O-])[O-])O)C)O)F)C.[Na+].[Na+]
- InChl (if other than submission substance): InChI=1S/C22H30FO8P.2Na/c1-12-8-16-15-5-4-13-9-14(24)6-7-19(13,2)21(15,23)17(25)10-20(16,3)22(12,27)18(26)11-31-32(28,29)30;;/h6-7,9,12,15-17,25,27H,4-5,8,10-11H2,1-3H3,(H2,28,29,30);;/q;2*+1/p-2/t12-,15-,16-,17-,19-,20-,21-,22-;;/m0../s1
- Structural formula attached as image file (if other than submission substance): see Fig.

Results and discussion

Any other information on results incl. tables

Placental transfer characteristics of betamethasone

Patient	Route of administration	D-D^a min	Cmv ng/ml	Cuv ng/ml	Cuv/Cmv
1	IV	56	83.9	22.9	0.27
2	IV	61	65.0	16.8	0.26
3	IM	116	29.8	7.7	0.26
4	IM	121	36.0	9.8	0.27
5	IM	137	67.2	19.8	0.29
6	IM	259	37.8	8.6	0.23
7	IM	321	34.7	12.7	0.37
8	IM	331	31.6	9.4	0.30
9	IM	377	43.4	13.8	0.32
10	IM	381	33.3	9.6	0.29
11	IV	800	15.2	3.6	0.24

^a Interval between the last dose and delivery

Cmv: Concentration on maternal vein

Cuv: Concentration umbilical vein

Applicant's summary and conclusion

Conclusions:

Betamethasone crosses placenta and it was detectable as unmetabolized free alcohol in approximately 25 to 30% of the concomitant maternal level.