[2R-(2α,3Z,5α)]-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, compound with tert-butylamine (1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: A company document which reviews several studies

Adequacy of study:

key study

Study period:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete or methodological deficiencies, which do not affect the quality of relevant results.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

1976

Report date:

1976

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

No information regarding the methods used have been provided in the clinical brochure, this is not the actual study report this is a review of studies which were conducted on the surrogate material (potassium clavulanate).

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

potassium clavulanate

IUPAC Name:

potassium clavulanate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Potassium clavulanate

Radiolabelling:

yes

Test animals

Species:

other: various different animals were used including a dog, rat, mouse and monkey

Strain:

other: As various animals were used, various species have been used too.

Sex:

male/female

Administration / exposure

Route of administration:

other: various routes including the oral route, subcutaneous, intravenous and intramuscular

Vehicle:

not specified

Duration and frequency of treatment / exposure:

no data

Doses / concentrations

Remarks:

Doses / Concentrations:
various concentrations were used:
In the urinary excretion studies the animals were tested at concentrations of 100 mg/kg.

In the metabolism studies, the mouse was tested at concentrations of 20, 50 and 100 mg/kg, the rat was tested at concentrations of 100 and 500 mg/kg, the dogs were tested at concentrations of 90 and 500 mg/kg and the monkeys were tested at concentrations of 10 and 100 mg/kg.

No. of animals per sex per dose / concentration:

no data available

Control animals:

not specified

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Mouse:
Absorption In the mouse appears to be variable. Blood concentrations of between 14 and 29 µg/ml were obtained after oral administration of 100 mg/kg. Subcutaneous administration at the same dose gave blood concentrations roughly five-fold higher than this (80 - 120 µg/ml).

Rat:
After orally dosing the rat with 100 mg/kg, blood concentrations were low, 0.9 to 2.9 µg/ml. Intramuscular administration of 500 mg/kg gave peak blood levels of 200 to 340 µg/ml after 15 to 30 minutes.

Dog:
Blood concentrations in the dog after oral administration of 90 mg/kg gave peak concentrations at 1 hour of between 17 and 33 µg/ml, but vomiting frequently occurs at this dose level. Intramuscular administration at 90 mg/kg resulted in higher blood concentrations, approximately three times greater
than from the corresponding oral dose occurring after 30 minutes. In repeat dose studies at 100 mg/kg similar results have been obtained indicating no accumulation of BRL. 14151.

Monkey:
Oral administration of BRL 14151 at 100 mg/kg to the squirrel monkey gave blood concentrations of 24 - 37 µg/ml. Intramuscular administration of 10 mg/kg produced blood concentrations of 10 to 15 µg/ml.

Details on distribution in tissues:

Extensive radioactive studies are currently being carried out to determine the route of excretion, the absorption and metabolism of BRL 14151 in the rat, dog, mouse and Rhesus monkey. At present the 14C-BRL 14151 used in these studies has been prepared by a fermentation process.

The information obtained so far indicates that in the rat the absorption of 14C-BRL 14151 or its metabolites after oral administration is greater than that indicated by the non-radioactive studies carried out where only BRL.14151 was measured in urine. The radioactive studies have also indicated that in the rat the bile is currently a minor route of elimination of the 14C-compound or its metabolites and that extensive metabolism of the 14C-BRL.14151 occurs when the compound is administered orally.

Details on excretion:

Mouse:
Urinary recovery figures are generally low/moderate (4 - 21% at 100 mg/kg) after oral dosing. After subcutaneous dosing, the urinary excretion is generally two to three fold higher than after the corresponding oral dose.

Rat:
The percentage urinary recovery Is low and extremely variable after oral administration to both Wistar and Sprague Dawley rats, (0.08 - 4.4% Wlstar and 0.5 - 9.6% for Sprague Dawley strain, after 100 mg/kg). Intramuscular administration also gave extremely variable urinary recoveries (ranging from 4 - 55% for Wistar and 8.3 - 77%. Sprague Dawley strain, after 500 mg/kg). A marked sex difference has been observed, female giving high recoveries In high urine volumes, males low recoveries in low urine volumes.

Dog:
Urinary recoveries are extremely variable after both oral and intramuscular dosing, ranging between 2.5 and 63% In separate studies after oral dosing and similar erratic recovery is seen after intramuscular dosing.

Monkey:
Urinary recovery after oral administration of 100 mg/kg was less than seen In the dog and mouse, but not as variable as seen in the rat.

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

This layer chromatography using non radiolabelled compounds has also been carried out in urine from the dog and the rat. Urine from dogs dosed with BRL 14151 at 100 mg/kg orally and intramuscularly showed a single spot with the same RF value as BRL 14151. The chromatograms from rat urine showed many spots, however BRL 14151 was not positively detected.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no data
The information obtained so far indicates that in the rat the absorption of 14C-BRL 14151 or its metabolites after oral administration is greater than that indicated by the non-radioactive studies carried out where only BRL.14151 was measured in urine. The radioactive studies have also indicated that in the rat the bile is currently a minor route of elimination of the 14C-compound or its metabolites and that extensive metabolism of the 14C-BRL.14151 occurs when the compound is administered orally.

Executive summary:

Several studies were conducted on a range of species including the rat, dog, mouse and monkey. The studies looked into adsorption, excretion, metabolism and distribution of potassium clavulanate within these animals. The results can be seen below:

Adsorption:

Mouse:

Absorption In the mouse appears to be variable. Blood concentrations of between 14 and 29 µg/ml were obtained after oral administration of 100 mg/kg. Subcutaneous administration at the same dose gave blood concentrations roughly five-fold higher than this (80 - 120 µg/ml).

Rat:

After orally dosing the rat with 100 mg/kg, blood concentrations were low, 0.9 to 2.9 µg/ml. Intramuscular administration of 500 mg/kg gave peak blood levels of 200 to 340 µg/ml after 15 to 30 minutes.

Dog:

Blood concentrations in the dog after oral administration of 90 mg/kg gave peak concentrations at 1 hour of between 17 and 33 µg/ml, but vomiting frequently occurs at this dose level. Intramuscular administration at 90 mg/kg resulted in higher blood concentrations, approximately three times greater

than from the corresponding oral dose occurring after 30 minutes. In repeat dose studies at 100 mg/kg similar results have been obtained indicating no accumulation of BRL. 14151.

Monkey:

Oral administration of BRL 14151 at 100 mg/kg to the squirrel monkey gave blood concentrations of 24 - 37 µg/ml. Intramuscular administration of 10 mg/kg produced blood concentrations of 10 to 15 µg/ml.

Urinary recovery values were low and very variable in all the specieis tested and through all the routes of administration tested (intramuscular and via te oral route).

The following results were obtained from radioactive studies to assess the distribution of potassium clavulanate:

The information obtained so far indicates that in the rat the absorption of 14C-BRL 14151 or its metabolites after oral administration is greater than that indicated by the non-radioactive studies carried out where only BRL.14151 was measured in urine. The radioactive studies have also indicated that in the rat the bile is currently a minor route of elimination of the 14C-compound or its metabolites and that extensive metabolism of the 14C-BRL.14151 occurs when the compound is administered orally.