Fusidic acid

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Remarks:

Clinical overview

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

other: Pharmacokinetics

Principles of method if other than guideline:

Clinical studies on orally administrated fusidic acid in humans.
1. Single dose, 500 mg film-coated tablets, adults
2. Three times a day, 500 mg oral formulation, adults
3. Single dose, 20 mg/kg and 10 mg/kg, oral suspension, children

GLP compliance:

no

Specific details on test material used for the study:

The clinical review covers sodium fusidate orally administrated in film-coated tablets, oral formulations and oral suspensions.

Species:

other: humans

Sex:

not specified

Route of administration:

oral: feed

Vehicle:

other: film-coated tablets, suspensions

Details on exposure:

1. Single dose, 500 mg film-coated tablets, adults
2. Three times a day, 500 mg oral formulation, adults
3. Single dose, 20 mg/kg and 10 mg/kg, oral suspension, children

Details on absorption:

1. Single dose, 500 mg film-coated tablets, adults: 90-95% absorbed, serum concentration exceeding 10 mg/L after 1 hour and maximum levels reaching 30 mg/L at 3 hours. Elimination half life 9-16 hours.
2. Three times a day, 500 mg oral formulation, adults: mean accumulated serum concentration of 71 mg/L
3. Single dose, 20 mg/kg and 10 mg/kg, oral suspension, children: Maximum serum concentration of 16.9 mg/L after 2.7 hours (10 mg/kg). Elimination half life 16 h and 7.4 hours, respectively.

Details on distribution in tissues:

Studies indicate that 90% of fusidic acid is reversibly bound to plasma proteins, fusidic acid distributes by diffusion into most tissues providing concentrations in various organs ranging from 20% to 90% of matching serum concentrations, and that 95% of a single dose is eliminated from serum over 24 hours via the bile.

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 9-16 hours

Remarks:

adults

Test no.:

#1

Toxicokinetic parameters:

C(time): 10 mg/L (1 hour)

Test no.:

#1

Toxicokinetic parameters:

Cmax: 30 mg/L (3 hours)

Metabolites identified:

not measured

Bioaccessibility (or Bioavailability) testing results:

1. Bioavailability of fusidate in tablets in adults is approximately 91%.
3. Bioavailability of fusidic acid in oral suspension administrated to children is 22.5% (20 mg/L) and 30-40% (10 mg/L)

Conclusions:

Approximately 90-95% of orally administrated sodium fusidate in a single dose is absorbed and maximum serum concentration levels are reached after approximately 3 hours. The studies indicate that 95% of a single dose is eliminated from serum over 24 hours via the bile.

Executive summary:

In a clinical review on sodium fusidate orally administrated in film-coated tablets, oral formulations and oral suspensions, it is indicated that 90-95% of a single dose of sodium fusidate is absorbed and maximum serum concentration levels are reached after approximately 3 hours. Bioavailability is approximately 91% in adults and lower (22.5 -40%) in children.

The elimination half life of sodium fusidate/fusidic acid in serum is 9 -16 hours. The studies indicate that 95% of a single dose is eliminated from serum over 24 hours via the bile.

Reference 2

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Study with eight male rabbits (New Zealand White). An area 6 cm x 10cm was shaved on the back of the rabbits. Four of the rabbits were treated with 1% sodium lauryl sulphate in vaseline. The remaining four rabbits were untreated. After 24 hours ca. 1g of salve was applied to the shaved area of all eight rabbits. Blood samples were taken after 0,2,4,6,8,24 and 48 hours after application.

GLP compliance:

no

Specific details on test material used for the study:

Salve containing 2% tritiated fucidin in fucidin salve (without lanolin) containing 0.68 mCi/g

Radiolabelling:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

Body weight between 2.55 and 3.05 kg.

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Duration of exposure:

48 hours

Doses:

1 g salve of 0.68 mCi/g

No. of animals per group:

8

Control animals:

no

Details on study design:

An area 6 cm x 10cm was shaved on the back of the rabbits. Four of the rabbits were treated with 1% sodium lauryl sulphate in vaseline. The remaining four rabbits were untreated. After 24 hours ca. 1g of salve was applied to the shaved area of all 8 rabbits. Blood samples were taken after 0,2,4,6,8,24 and 48 hours after application. The animals were kept in stocks for the first 24 hours after application.

Serum was prepared from the blood samples. The serum samples were counted for up to 50 minines each in a Beckman CPM-100 liquid scintillation counter. Counting efficiency was determined from a previously prepared external standard quench correction curve.

Absorption in different matrices:

Counts in serum from rabbits pretreated with lauryl sulphate were 3-45 times greater than in blank serum. In the untreated rabbits, many of the counts were less than twice blank.
Mean levels in the pretreated rabbits were roughly 10 times levels in the untreated animals. The highest single concentration obtained in any animal whilst in the stocks was 3.4 % dose/rabbit in pretreated animals, and 0.16% in intact animals.

The % dose absorbed was calculated assuming a distribution volume of 1 L/kg and was in pretreated rabbits 0.2-3.4% dose/rabbit and 0.02-0.16% in intact animals.

Mean % dose/rabbit at various time after dosing

Rabbit	2 hours	4 hours	6 hours	8 hours	24 hours
1 - pretreated	0.547	0.702	3.357	0.790	1.824*
2 - pretreated	2.023	0.911	1.195	1.174	0.737
3 - pretreated	0.300	0.965	0.356	0.322	0.200
4 - pretreated	0.692	0.694	0.630	0.416	0.210
Mean - pretreated	0.891	0.818	1.454	0.676	0.743
5 - unchanged skin	0.033	0.116	0.088	0.101	2.284*
6 - unchanged skin	0.040	0.078	0.076	0.084	0.069
7 - unchanged skin	0.045	0.047	0.114	0.065	0.155
8 - unchanged skin	0.015	Not valid	0.028	0.020	0.073
Mean - unchanged skin	0.033	0.080	0.077	0.068	0.0645

* Removed from stocks after 8 hours

Only blood samples obtained at times when the rabbit is confined in stocks are a valid expression of cutaneous absorption, since samples obtained later (48 hour) were in general higher and this is taken as evidence of oral absorption.

Counts in serum from rabbits pretreated with lauryl sulphate were 3-45 times greater than in blank serum. In the untreated rabbits, many of the counts were less than twice blank.

Mean levels in the pretreated rabbits were roughly 10 times levels in the untreated animals. The highest single concentration obtained in any animal whilst in the stocks was 3.4 % dose/rabbit in pretreated animals, and 0.16% in intact animals.

Conclusions:

The dermal absorption of sodium fusidate is very low, 0.02-0.16% based on results from a study in rabbits.

Executive summary:

A dermal absorption study Study with eight male rabbits (New Zealand White) was performed. An area 6 cm x 10cm was shaved on the back of the rabbits. Four of the rabbits were treated with 1% sodium lauryl sulphate in vaseline. the remaining four rabbits were untreated. After 24 hours ca. 1g of salve was applied to the shaved area of all 8 rabbits. Blood samples were taken after 0,2,4,6,8,24 and 48 hours after application.

Serum levels in pretreated rabbits were 3-45 times greater than in blank serum. Levels in animals with intact skin were substantially lower.

The % dose absorbed was calculated assuming a distribution volume of 1 L/kg and was in pretreated rabbits 0.2-3.4% dose/rabbit and 0.02-0.16% in intact animals.  

Description of key information

Human toxicokinetic data from oral administration available. In a clinical review on sodium fusidate orally administrated in film-coated tablets, oral formulations and oral suspensions, it is indicated that 90-95% of a single dose of sodium fusidate is absorbed and maximum serum concentration levels are reached after approximately 3 hours. Bioavailability is approximately 91% in adults and lower (22.5 -40%) in children.

The elimination half life of sodium fusidate/fusidic acid in serum is 9 -16 hours. The studies indicate that 95% of a single dose is eliminated from serum over 24 hours via the bile.

Absorption data from dermal study in rabbits available. A study with eight male rabbits (New Zealand White) was performed. Four of the rabbits were treated with 1% sodium lauryl sulphate in vaseline. the remaining four rabbits were untreated. After 24 hours ca. 1g of salve was applied to the shaved area of all 8 rabbits. Blood samples were taken after 0,2,4,6,8,24 and 48 hours after application.

Serum levels in pretreated rabbits were 3-45 times greater than in blank serum. Levels in animals with intact skin were substantially lower. The % dose absorbed was calculated assuming a distribution volume of 1 L/kg and was in pretreated rabbits 0.2-3.4% dose/rabbit and 0.02-0.16% in intact animals.  

Available data from human and animal studies indicate high (95%) and very low (0.16%) absorption from oral and dermal administration, respectively with a low potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

95

Absorption rate - dermal (%):

0.16

Absorption rate - inhalation (%):

0