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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented materials and methods section with appropriate number of animals per group and time point. No controls used. Only 1 dose group. Did not include excretion, or metabolism parameters. No GLP compliance reported.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Gender Differences in Pharmacokinetics of Oral Warfarin in Rats
Author:
Zhu X, Shin WG
Year:
2005
Bibliographic source:
Biopharmaceutics and Drug Disposition, 26: 147-150

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
The purpose of the study is to determine gender differences in the pharmacokinetics of oral warfarin in rats.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Warfarin.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Samtako Bio Korea (Seoul, Republic of Korea.)
- Age at study initiation: 7 weeks.
- Weight at study initiation: 250-320 grams.
- Fasting period before study: Overnight.
- Individual metabolism cages: Yes.
- Diet: Ad libitum.
- Water: Ad libitum.



ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23 degrees Celcius.
- Humidity (%): 50%.
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark.


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The procedures for the pretreatment of rats including the cannulation of the carotid artery in the early morning of the experiment were reported previously. Rats were lightly anaesthetized with ether and the experiment was started 4–5 hours after surgery. Warfarin was administered orally (total oral volume of approximately 1.5 ml) to male and female rats using a feeding tube.
Doses / concentrations
Remarks:
Doses / Concentrations:
2mg/kg.
No. of animals per sex per dose:
10 per sex per same dose.
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: Blood.
- Time and frequency of sampling: Approximately a 0.22 ml blood sample was collected via the carotid artery in an Eppendorf tube containing a 30 ml aliquot of 3.8% sodium citrate (to prevent blood clotting) at 0 (to serve as a control), 0.5, 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours. Blood samples were centrifuged immediately and a 100 ul aliquot of each plasma sample was stored in a -70 degrees Celcius freezer until HPLC analysis.

- Other: The concentrations of warfarin in the above plasma samples were analysed by the reported HPLC method (1.)

Statistics:
A value of p<0.05 was considered to be statistically significant using an unpaired t-test. All data are expressed as mean +/- standard deviation.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
AUC: 180 +/-52.0 in males; 345+/-80.0 in females
Test no.:
#2
Toxicokinetic parameters:
Cmax: 7.13+/-3.12 in males; 7.53+/-1.29 females
Test no.:
#3
Toxicokinetic parameters:
Tmax: 6 in males; 12 in females
Test no.:
#4
Toxicokinetic parameters:
other: Terminal half-life in males = 16.1+/-5.43; in females = 28.4 +/-8.32

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

After oral administration of warfarin to male and female rats, concentrations declined thereafter (Cmax) in a monoexponential fashion for all rats studied. In female rats, the plasma concentrations of warfarin were higher after Tmax than those in male rats. This resulted in a significantly greater AUC of warfarin in female rats (91.7% increase).

The slower metabolism of warfarin in female rats could be at least partly supported by the significantly longer terminal half-life of warfarin (76.4% increase). In female rats, the plasma concentrations of warfarin were lower up to Tmax and the Tmax was significantly longer (78.5% increase) suggesting that warfarin is absorbed more slowly in female rats.

Table 1

Mean (+/- standard deviation) pharmacokinetic parameters of warfarin

after oral administration at a dose of 2mg/ kg to male and female rats

Parameter

Male (n = 10)

Female (n= 10)

AUC (ug h/ml)

180 +/- 52.0a

345 +/- 80.0

Cmax (ug/ml)

7.13 +/- 3.12

7.53 +/- 1.29

Tmax (h)b

6 (1-12)c

12 (8-24)

Terminal half-life (h)

16.1 +/- 5.43a

28.4 +/- 8.32

aSignificantly different (p<0.001) from female rats.

bMedian (range).

cSignificantly different (p<0.05) from female rats

Applicant's summary and conclusion

Conclusions:
After oral administration of warfarin to female rats, the AUC was significantly greater (345 compared with 180 ug h/ml) than that in male rats.