open access

Vol 19, No 6 (2014)
Original research articles
Published online: 2014-11-01
Submitted: 2013-10-25
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The mutagenicity analysis of imidapril hydrochloride and its degradant, diketopiperazine derivative, nitrosation mixtures by Ames test with two strains of

Katarzyna Regulska, Marek Murias, Beata Stanisz, Miłosz Regulski
DOI: 10.1016/j.rpor.2014.04.004
·
Rep Pract Oncol Radiother 2014;19(6):412-419.

open access

Vol 19, No 6 (2014)
Original research articles
Published online: 2014-11-01
Submitted: 2013-10-25

Abstract

Aim

The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used.

Background

IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard.

Materials and methods

Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the presence and absence of metabolic activation system (S9 mix) using a commercial Ames MPF 98/100 microplate format mutagenicity assay kit.

Results

None of the six concentrations of the investigated nitrosation mixtures exhibited any mutagenic potential in both S. typhimurium strains. The addition of S9 mix did not alter the non-mutagenic properties of the studied compounds.

Conclusions

The nitrite treatment of both studied compounds has no impact on their mutagenic properties under the conditions of the present studies. Hence, IMD and DKP nitrosation mixtures are classified as non-mutagens in this test.

Abstract

Aim

The evaluation of mutagenic properties of imidapril hydrochloride (IMD) and its degradation impurity, diketopiperazine derivative (DKP), nitrosation mixtures was conducted in order to analyze the carcinogenic risk of IMD long-term treatment in patients. In this study an in vitro Ames test with Salmonella enterica serovar Typhimurium TA 98 and TA 100 strains was used.

Background

IMD and DKP contain nitrogen atoms, which makes them theoretically vulnerable to in vivo nitrosation with the production of N-nitroso compounds (NOC). NOC, in turn, are known animal mutagens indicating that their endogenous production from nitrosable drugs constitutes a carcinogenic hazard.

Materials and methods

Pure IMD sample was exposed to forced degradation conditions of increased temperature and dry air in order to achieve a DKP sample. Both samples were then treated with a nitrosating agent and the obtained nitrosation mixtures were subjected to mutagenicity analysis by the Ames test with S. typhimurium TA 98 and TA 100 strains in the presence and absence of metabolic activation system (S9 mix) using a commercial Ames MPF 98/100 microplate format mutagenicity assay kit.

Results

None of the six concentrations of the investigated nitrosation mixtures exhibited any mutagenic potential in both S. typhimurium strains. The addition of S9 mix did not alter the non-mutagenic properties of the studied compounds.

Conclusions

The nitrite treatment of both studied compounds has no impact on their mutagenic properties under the conditions of the present studies. Hence, IMD and DKP nitrosation mixtures are classified as non-mutagens in this test.

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Keywords

Angiotensin-converting enzyme inhibitors; Degradation; N-nitroso compounds; Mutagens

About this article
Title

The mutagenicity analysis of imidapril hydrochloride and its degradant, diketopiperazine derivative, nitrosation mixtures by Ames test with two strains of

Journal

Reports of Practical Oncology and Radiotherapy

Issue

Vol 19, No 6 (2014)

Pages

412-419

Published online

2014-11-01

DOI

10.1016/j.rpor.2014.04.004

Bibliographic record

Rep Pract Oncol Radiother 2014;19(6):412-419.

Keywords

Angiotensin-converting enzyme inhibitors
Degradation
N-nitroso compounds
Mutagens

Authors

Katarzyna Regulska
Marek Murias
Beata Stanisz
Miłosz Regulski

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