Imidazole

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets accepted scientific standards and is described in sufficient detail.

Data source

Reference

Reference Type:

publication

Title:

Pharmacokinetic profile of imidazole 2-hydroxybenzoate, a novel nonsteroidal antiinflammatory agent.

Author:

Kuemmerle H-P et al.

Year:

1987

Bibliographic source:

Int J Clin Pharm Ther Toxicol 24: 581-597

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

This was a crossover study with four different groups for tablets and drops (single and multiple dosing). Each group consisted of 18 healthy,male volunteers between 18-25 years of age having within 20 % of their ideal body weight. Informed written consent was given after the
purpose of the study and the nature of the compound was explained.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Imidazole

EC Number:

206-019-2

EC Name:

Imidazole

Cas Number:

288-32-4

Molecular formula:

C3H4N2

IUPAC Name:

1H-imidazole

Details on test material:

ITF 182 (antiinflammatory drug) containing equimolar quantities of imidazole and 2-hydroxybenzoate

Drug formulation
Tablets: Imidazole 2-hydroxybenzoate tablets were used containing 750 mg of the active compound, lactose, microcrystalline cellulose, carboxy-methylstarch, PVP and Mg stearate. The tablets were swallowed with tap water.
Drops (40 % solution, 40 drops = 800 mg) consisted of imidazole 2-hydroxybenzoate (400 mg), Glycerol (180 mg), Lemon flavor (0.02 ml), Saccharin sodium (10 mg), Sodium chloride (10 mg), purified water (0.52 ml)

Radiolabelling:

no

Test animals

Species:

human

Sex:

male

Details on test animals or test system and environmental conditions:

4 groups of healthy male volunteers attended the study. Age ranged between 18-25 years. Body weight was within 20% of their ideal body
weight.

Administration / exposure

Route of administration:

other: oral tablet and/or drops

Vehicle:

unchanged (no vehicle)

Details on exposure:

Male probands received 1 tablet (containing 750 mg drug) or 40 drops (containing 400 mg drug) in the morning after fasting overnight in the single dose study. In the crossover multiple dosing study they received 3 times one tablet (or 3 times 40 drops) for 3 days and one dosing inthe morning of the 4th day.

Duration and frequency of treatment / exposure:

see "details on exposure"

Doses / concentrations

Remarks:

Doses / Concentrations:
750 mg of drug (containing 248 mg imidazole), or 3 times 750 mg drug/day for 3 -4 days (10 treatments)

No. of animals per sex per dose / concentration:

not applicable

Control animals:

other: not applicable

Details on dosing and sampling:

Medical, biochemical, and hematological examination was performed before and after the study.
Blood sampling - single dosing
0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225, 240, 360, 480 min and 24 h after administration
Blood sampling - multiple dosing
15, 30, 45, 60, 90, 120, 180, 240 min and 5, 6, 7, 8, 9, 10, 12 h, and thereafter every 12 hours. After the last dose on day 4 blood samples were taken at 0, 30, 60, 90, 120, 180, 240, 300, 360, min and 8, 24, 36 hours.

Urine sampling periods were 0-2, 2-4, 4-6, 6-8, 8-24, 24-36 and 36-48 h after single dosing.
In the multiple dosing study periods were 0-12 and 12-24 h for days 1, 2 and 3; for day 4 periods were the same as after single dosing.

Clinical chemistry included bilirubin, transaminases, alcaline phosphatase, LDH, gamma-GT, triglycerides, cholesterol, creatinine, uric acid, glucose, total protein, albumine, globuline, sodium, potassium, chloride.
Hematology included red blood cell count, hemoglobin, hematocrit, leucocytes including differential count, and platelets.

Imidazole was analyzed with HPLC.

Statistics:

Descriptive statistics included calculation of means, standard deviations, medians, minima and maxima. The means and the p-values
between the application of imidazole and salicylic acid were calculated according to a paired Wilcoxon-test.

Results and discussion

Preliminary studies:

In a pilot study imidazole 2 - hydroxybenzoate was applied as a 5% gel (82 mg Imidazole in 5 g gel) to the forearm skin
(area about 25 cm²) of four male volunteers to determine possible systemic influence. Neither imidazole 2 - hydroxybenzoate nor
imidazole, salicylic acid or salicyluric acid were found in urine up to 12 hours after application. Plasma samples were not examined.
No adverse effects were seen either locally or systemically

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The parameters clearly show that peak plasma concentrations were rapidly attained following single or multiple administration of tablets or
drops, thus indicating fast absorption.

Details on distribution in tissues:

not applicable

Details on excretion:

Renal elimination of imidazole was approx. 10 to 15 % of the dose.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Cmax: 3.445 (mean; single dose tablets + drops)

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

Tmax: 0.75 (mean; single dose tablets + drops)

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

AUC: 14.145 (mean; single dose tablets + drops)

Toxicokinetic parameters 4

Test no.:

#1

Toxicokinetic parameters:

half-life 2nd: 2.73 (mean; single dose tablets + drops)

Toxicokinetic parameters 5

Test no.:

#2

Toxicokinetic parameters:

Cmax: 2.705 (mean; multiple dose tablets + drops)

Toxicokinetic parameters 6

Test no.:

#2

Toxicokinetic parameters:

Tmax: 0.595 (mean; multiple dose tablets + drops)

Toxicokinetic parameters 7

Test no.:

#2

Toxicokinetic parameters:

AUC: 8.165 (mean; multiple dose tablets + drops)

Toxicokinetic parameters 8

Test no.:

#2

Toxicokinetic parameters:

half-life 2nd: 1.99 (mean; multiple dose tablets + drops)

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The metabolites hydantoin and hydantoic acid were present in plasma and urine, although below the limit of detection as
no radioactive label was used.

Any other information on results incl. tables

Pharmacokinetic parameters of imidazole following oral
dosing (tablet and drops combined, means):

                    single dose       multiple dose
                  ------------------------------            
Cmax (mg/l)        3.445 (tablet+drops)       2.705(tablet+drops)       
Tmax (h)           0.75  (tablet+drops)       0,595(tablet+drops)        

t1/2ß (h)          2.73                       1.99
protein (% of dose)      5 - 15%
binding
bioavailability       138%                    113%
---------------------------------------------
Legend:
Cmax  maximum concentration (mg/l) 
t1/2ß elimination half-life (h)

No statistically significant difference was noted between tablets and drops 
treatment, only one p-value was < 0.01. Tolerability was good, no adverse 
reactions were noted. Topical application (gel 5%) did not show any systemic 
effects or adverse reactions. Local tolerability was reported to be very good.

Applicant's summary and conclusion

Executive summary:

Pharmacokinetic parameters for imidazole are presented from single and multiple oral dose studies. No differences were noted between administration as tablet or as drops. Pharmacokinetic parameters were very similar in both the single and multiple dose

study. Imidazole is rapidly absorbed and excreted. Bioavailability is high, protein binding is low.

It is concluded from these data that bioaccumulation is unlikely.