Hydromorphone impurity 2,2-bishydromorphone does not exert mutagenic and clastogenic properties via in silico QSAR prediction and in vitro Ames and micronucleus test

Abstract

The opioid agonist hydromorphone is indicated for the management of severe acute and chronic pain given that alternate treatments are insufficient. While the genotoxicity profile of hydromorphone is well investigated, little is known about the genotoxic potential of its impurities. In this study, 2,2-bishydromorphone was tested in silico and in vitro for both its mutagenic potential in an Ames test performed with Salmonella typhimurium and Escherichia coli tester strains up to a maximum concentration of 5 mg per plate in the absence and presence of metabolic activation. Furthermore, it was tested for its ability to induce micronuclei in TK6 cells in a micronucleus test up to a maximum concentration of 500 µg/mL with or without an exogenous metabolic activation system. 2,2-Bishydromorphone did not reveal any potential for inducing mutagenicity or clastogenicity under the conditions of the respective tests and is therefore considered non-mutagenic and non-clastogenic/aneugenic in vitro. These results are in line with negative in silico quantitative structure-activity relationship (QSAR) prediction for 2,2-bishydromorphone mutagenicity and clastogenicity and provide evidence of good correlation of in silico and in vitro data. Conclusively, these studies add important new clinically relevant information on the safety of hydromorphone as the impurity of 2,2-bishydromorphone is proven to be non-mutagenic and non-clastogenic.

Keywords:

• Hydromorphone
• impurity
• mutagenicity
• clastogenicity
• intravenous
• AMES
• micronucleus test
• QSAR

Acknowledgements

We thank the following employee of Charles River Skokie, USA for her participation in the study: Nikita D. Navalkar for formulation analysis of the test item.

Author contributions

DF and MKB designed the study and interpreted the data. SBH conducted the in vitro experiments. DF drafted the article and MKB, MW, and SBH revised it critically and finally approved the version to be submitted.

Disclosure statement

The authors report no conflict of interest. DF, MKB, and MW are employees of Fresenius Kabi Deutschland GmbH.