Amitraz - Metabolism

Metabolism

Since amitraz most common use is as a pesticide, it is important to consider that between animals and plants often different pathways for biotransformation occur. Most animal species, including humans can metabolize amitraz rapidly to form six metabolites during biotransformation, N-Methyl-N'-(2,4-xylyl)formamide, Form- 2'4'xylidine, 4-N-Methyl-formidoyl) amino-meta-toluix acid, 4-Formamido-meta-toluic acid, 4- Acetamido- meta-toluic acid and 4- Amino- meta- toluic acid.11, 12, 13

In rats the metabolic pathway (figure 3) has been examined after oral administration of 14C-labelled amitraz, which was found to be effectively metabolized, degraded and excreted to four of the metabolites in urine and six in faeces.12 The metabolic pathway or rate did not differ between the sexes.

Hornish and Nappier (1983) detected that the metabolic pathway after dermal administration follows the same route of degradation as after oral uptake, because the parent compound, N-methyl- N'-(2,4-xylyl)formamidine and form-2',4'-xylidide were found in urine and blood also after dermal administration.12 In humans N-methyl- N-(2,4-xylyl)formamidine, form-2',4'-xylidide, 4-amino- meta-toluic acid, 4-acetamido- meta-toluic and 4-formamido- meta-toluic acids were recognized in the urine as well which indicates for the same or a similar metabolic pathway.13

As illustrated in figure 3 the first step is a hydrolysis reaction to N-methyl- N'-(2,4-xylyl)-formamidine, which already can be excreted in the urine but is still pharmacological active.12, 13 Depending on the dose, the quantity of this metabolite in the urine can vary from 4% at low doses to 23%-38% at high doses (e.g. in case of rats: 1–100 mg per kg body weight).12 As it isn't excreted it also can be oxidized to 4-N-Methyl-formidoyl)amino-meta-toluic acid, which can be further oxidized to 4-formamido-meta-toluic acid.12 Form-2,4-xylidine is formed directly by hydrolysis from amitraz or arises from N-methyl- N'-(2,4-xylyl)formamidine.13 During this early stage of biotransformation N-methyl- N'-(2,4-xylyl) formamidine and Form-2,4-xylidine may already form conjugates.12 But the major route followed after the formation of Form-2,4-xylidine is the oxidation to 4-formamido-meta-toluic acid, which is further metabolized to its acetyl conjugate, 4-acetamido-meta-toluic acid or 4-amino- meta-toluic acid.12, 13 4-formamido- meta-toluic acid and 4-acetamido- meta-toluic acid make 32% of the metabolites found in urine and are detected at any administered dose. Therefore they are considered as two of the major metabolites in the amitraz pathway.12 Form-2',4'-xylidide and 4-amino- meta-toluic acid account only for 2% of the total excretion.12 In insects different metabolites are formed. N-methyl- N'-(2,4-xylyl)formamidine, Form-2,4-xylidine and 4-Amino-meta-toluic acid occur, but in addition several unidentified metabolites were detected, too.13

In plants the biotransformation of amitraz proceeds very rapidly. The predominant metabolites detected are N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) and 2,4-dimethylformanilide (BST 27 919).8

N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271), 2,4-dimethylformanilide (BST 27 919) and N,N'-bis-dimethylphenylformamidine (BTS 28 037) result from hydrolysis of amitraz. Thereby N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) occurs in higher amounts than 2,4-dimethylformanilide (BST 27 919). N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) can be further metabolized to 2,4-dimethylformanilide (BST 27 919) or 2,4-dimethylaniline (BTS 24 868).8

N,N'-bis-dimethylphenylformamidine (BTS 28 037) can be transformed to 2,4-dimethylformanilide (BST 27 919) or directly react to 2,4-dimethylaniline (BTS 24 868), but the exact mechanisms of these biotransformations are not known yet.8 However, of 2,4-dimethylaniline (BTS 24 868) and N,N'-bis-dimethylphenylformamidine (BTS 28 037) less than 1% has been accounted, which makes them minor metabolites compared to N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) and 2,4-dimethylformanilide (BST 27 919).8 Figure 4 shows the suggested amitraz' metabolic pathway in plants.8