N-cyclopropyl-4-[(2-methoxybenzoyl)sulfamoyl]benzamide

Endpoint summary

Additional information

In order to determine the distribution of N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide,male rats were orally administered with a target dose of 5 mg/kg bw of radioactive test substance, either uniformly labelled with 14C in the sulfonylbenzamide- or in the methoxybenzoyl-ring of the molecule, in two independent studies. After an observation period of up to 168 hours quantitative whole body autoradiography (QWBA) was performed.

In both studies the test substance was absorbed quickly from the gastrointestinal tract and featured high bioavailability. The maximum concentration of radioactivity in almost all organs and tissues was found 1 hour after the administration. The absorption process was apparently discontinuous, probably due to delayed gastric emptying occurring between 4 and 48 hours after dosing. The high radioactivity observed in kidney already 1 hour after dosing indicated that renal excretion commenced immediately after absorption.

The absorbed radioactivity was not uniformly distributed in the body. At all time-points examined, high radioactivity was mainly observed in the excretory organs kidney and liver. The residues in all other organs and tissues were fairly evenly distributed and always lower than the residues observed in blood.

Residues in all organs and tissues decreased rapidly between 1 and 72 hours. In all organs and tissues residues were below the limit of detection (LOD) or quantification (LOQ) at later time-points between 72 and 168 hours after dosing. There was no sign for retention of radioactivity in specific organs or tissues. Residues from glandular organs or tissues responsible for hormonal regulation (such as adrenal, testis, or thyroid gland) were rapidly depleted in parallel with depletion from the other organs and tissues. The test substance was rapidly eliminated from the body, predominantly via renal excretion. Excretion was almost complete at the end of the study period. No significant expiration of 14C-labelled volatiles was observed.

 

In addition, the biokinetic behaviour and metabolism of N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide was investigated in two separate studies in the rat using either the [sulfonylbenzamide-ring-UL-14C]- or the [methoxybenzoyl-ring-UL-14C]-labelled compound. In the first study performed with the [sulfonylbenzamide-ring-UL-14C]-labelling a single high dose of 200 mg/kg bw and a single low dose of 2 mg/kg bw test substance were administered to male and female rats. Since no significant amounts of label-specific metabolites were formed and no significant sex differences were apparent, no tests with female rats or high dose levels were included in the study using the compound radiolabelled in the methoxybenzoyl moiety.

The absorption of the test substance was fast in all tests and commenced immediately after oral administration. The maximum plasma concentration was reached within 1 hour after administration. Double peak phenomena in the plasma profiles of the high dose tests and a discontinuous excretion pattern indicated delayed gastric emptying of a portion of the dose. Absorption in the low dose tests was nearly complete; 82% and more of the dose recovered was renally excreted or remained in the body at sacrifice (without gastrointestinal tract).

The distribution of the test substance into organs and tissues was followed using plasma kinetics. The plasma concentrations in all tests declined to less than 1% of the maximum concentration within 72 hours post administration, indicating that no retention of the compound related residues in the body of the animals took place.

Elimination of the test substance was rather fast and efficient in all tests as illustrated by the short terminal half-lives of the radioactive residues in the plasma in the range of 13 to 23 h. Nevertheless, large proportions of compound-related radioactivity were excreted 24 hours after administration in the high dose tests indicating delayed gastric emptying. Residues in tissues and organs at sacrifice were very low.

N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxybenzamide was metabolised only to a low extend. The parent compound (AE 0001789) was the main component detected in urine and faeces, accounting in all tests for more than 76% of the dose administered. Independent of the radiolabelled position, AE 0001789-descyclopropylamino was the major metabolite detected (2.37-7.93% of administered dose). Furthermore, the minor metabolite AE 0001789-desmethyl was verified in all tests. The second minor metabolite differed, depending on whether the test substance was radiolabelled in the methoxybenzoyl or the sulfonylbenzamide moiety. Administration of [sulfonylbenzamide-ring-UL-14C]-AE 0001789 resulted in AE 0001789-cyclopropylsulfamoylbenzamide, whereas administration of [methoxybenzoyl-ring-UL-14C]-AE 0001789 lead to AE 0001789-anisic acid.

 

The main metabolic reactions of AE 0001789 observed in the rat are:

• Elimination of the cyclopropylamine moiety by hydrolysis of the carboxamide bond in the sulfonylbenzamide moiety to give AE 0001789-descyclopropylamino,

• desmethylation of the methoxybenzoyl moiety,

• hydrolytic cleavage of the carboxamide bond in the methoxybenzoyl moiety of

a) the parent compound to form AE 0001789-cyclopropylsulfamoylbenzamide and AE 0001789-anisic acid or of

b) AE 0001789-desmethyl to form AE 0001789-cyclopropylsulfamoylbenzamide alone.

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