Imidazole

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Basic toxicokinetics:

The pharmacokinetic profile, protein binding, relative bioavailability and metabolism of imidazole as the main component of the nonsteroidal antiinflammatory agent imidazole-2hydroxybenzoate was studied in male subjects after single and multiple oral administration of tablets or drops. Groups of healthy male subjects (aged 18 to 25 years) of ideal body weight (within 20%), underwent comprehensive medical, biochemical and haematological examination before and after substance administration. They were given one 750 mg tablet (containing 750 mg imidazole 2 -hydroxybenzoate) or a single dose of 40 drops (containing a total of 400 mg imidazole 2 -hydroxybenzoate). In the multiple-dose study, the subjects received three times one tablet or three times 40 drops/day for another two days starting 48 hours after the initial dose. On study day 4, only the morning dose was administered. Very large numbers of blood and urine samples were collected and comprehensive laboratory tests were performed. The maximum concentration (Cmax) of imidazole observed after single and multiple administration of the two dosage forms (tablets and drops), the times to maximum concentration (Tmax), and the plasma half-lives are summarised in the following table:

	Single administration		Dose	Multiple administration
	Tablets	Drops		Tablets	Drops
C max^1	3.59 +/- 0.96	3.3 +/- 1.22	A	2.87 +/- 0,84	2.67 +/- 1.22
			B	3.11 +/- 0.78	2.30 +/- 0.61
T max^2	0.79 +/- 0.54	0.71 +/- 0.59	A	1.04 +/- 0.5	0.96 +/- 0.67
			B	0.68 +/- 0.51	0.51 +/- 0.52
T 1/2	2.89 +/- 1.13	2.48 +/- 1.19	A	2.85 +/- 1.25	3.47 +/- 2.64
			B	1.86 +/- 0.78	2.12 +/- 0.91

¹ µg imidazole/ml plasma

² time to C max, in hours

A: first dose

B: 10th (last) dose

The parameters clearly show that peak plasma concentrations were rapidly attained following single or multiple administration of tablets or drops, thus indicating fast absorption. Plasma levels dropped very rapidly after attainment of the peak plasma concentration. The plasma half-lives of the two dosage forms were similar and no signs of accumulation were observed. Imidazole 2 -hydroxybenzoate, the originally administered salt of imidazole and salicylic acid, was not found in the monodrug form in either plasma or urine. Renal elimination of imidazole was approx. 10 to 15 % of the dose. The protein binding of imidazole was 5 to 15%. The metabolites hydantoin and hydantoic acid were below the level of detection as no radioactive label was used. The decrease in plasma half-life seen after multiple administrations led the investigators to assume that imidazole had an enzyme inducing effect. The relative bioavailabilities of imidazole after single and multiple administrations were calculated as 138% and 113%, respectively. 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 (Kuemmerle et al., 1986).

Following single oral administration of imidazole to Wistar rats (aged 2 months, n=4 -5) at 0.24 mmol/kg body weight (equivalent to 16.3 mg/kg body weight), plasma imidazole levels were 8.9 µg/ml after 0.25 and 0.5 hours, 6.1 µg/ml after 1 hours and 2.0 µg/ml after 2 hours. Imidazole was no longer detectable in plasma at 4 hours after administration. The limit of detection was 0.02 mmol/l (equivalent to 1.36 µg/ml; Pagella et al., 1983).

Male Wistar rats (180 -200g) treated with single intravenous dose of 3 µmol (150 µCi) [2 -¹⁴C]-imidazole excreted 14.0 +/- 2% of the radioactivity as unchanged imidazole, 38.7 +/- 0.7% as hydantoin, 31.0 +/- 1.2% as hydantoic acid and 4.0 +/- 0.4% as additional, structurally unidentified metabolites in the urine within the first 24 hours after administration. Pretreatment with the cytochrome P450 inhibitor SKF525 -A increased the excretion of unmetabolized imidazole while at the same time reducing hydantoin and hydantoic acid, whereas pretreatment with the cytochrome P450 inducers 3 -methylcholanthrene and phenobarbitone had no significant effect on urinary metabolites. The residual radioactivity at 24 hours after administration, given as nmol equivalents based on the amount of imidazole/g tissue or per ml body fluid, was located primarily in the liver (approx. 0.35 nmol/g), kidneys (approx. 0.12 nmol/g) and aorta (approx. 0.1 nmol/g). The levels of radioactivity found in plasma, blood, heart, lung, brain, muscle skin and cartilage were all below approx. 0.03 nmol per g or ml. The fatty tissue contained no detectable radioactivity. More detailed studies of the radioactivity retained in the aortic tissue revealed that it was essentially bound to elastin and that binding was enhanced by pretreatment with SKF525 -A but was not affected by 3 -methylcholanthrene or phenobarbitone. In in-vitro studies, the radioactivity bound to elastin in the aortic tissue was dependent on cupro-ascorbate-catalysed reactions (Ohta et al., 1996, 1998)

The administration of 750 mg imidazole 2-hydroxybenzoate as a tablet or suppository produced respective peak imidazole plasma concentrations 3.4 +/- 0.26 and 2.78 +/- 0.25 µg/ml in 10 healthy subjects (4 men, 6 women). Maximum plasma concentrations were observed after 86.3 +/- 10.9 minutes (tablet) and 75.2 +/- 5.4 minutes (suppository). The half-lives of elimination from plasma were 1.70 +/- 0.19 hours (tablet) and 1.78 +/- 0.26 hours (suppository). Plasma samples were collected before administration and at 30, 60, 90, 120, 240, 360 and 480 minutes after administration (Noseda et al., 1988).

The available pharmacokinetic studies in rat and human demonstrate that imidazole is rapidly and quantitatively absorbed after oral administration and metabolized in the liver to the main metabolites hydantoin and hydantoic acid. The half-live of elemination from human plasma was between 1.7 and 3.0 hours after a single dose. Imidazole did not accumulate in the body. Renal excretion was the predominant route of elimination. In the rat 88 % of the administered radioactivity was eliminated in the urine within 24 hours as imidazole (14%), hydantoin (39%), hydantoic acid (31%) and unidentified metabolites (4%). After dermal application of imidazole 2 -hydroxybenzoate to human volunteers, neither the parent coumpound nor any metabolite were found in urine, indicating that bioavailability after dermal application is less than after oral administration.

Dermal absorption:

According to OECD guideline 428 and GLP, the diffusion of 14C-Imidazol into and through human skin was assessed by single topical application. Target doses of 1000 μg/cm² and 100 μg/cm² were applied to split thickness skin preparations mounted on Franz-type diffusion cells. After the exposure time of 8 h and after the sampling period (24 hours after exposure), skin membranes were washed with a mild soap solution and tap water. At the end of the sampling period the test substance was recovered from all compartments of each diffusion cell. The mean total recoveries fulfill the quality criteria put forward in the test guidelines. The mean absorbed doses were 92.09 and 67.66% of dose for skin treated with the high dose and the low dose, respectively. For all dose groups, minor amounts of the test substance were associated with the skin after the exposure period. These amounts accounted to 1.15 and 2.00 % of dose for the high dose and the low dose, respectively. Mean absorption lag times were 1.07 hours and 1.37 hours for the high and low dose, respectively, and demonstrate the presence of a functional barrier in the skin samples used (BASF SE 2013).