Pharmacology

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Ames reverse mutagenicity assay

Mutagenicity is closely linked to carcinogenicity and is a major concern when designing new drug molecules. In accordance with FDA and OECD 471 guidelines we test all biologically relevant new derivatives using an Ames MPF Penta kit (Xenometrix) with five bacterial strains (TA98, TA100, TA1535, TA1537, Salmonella strains and the combination of E.coli uvrA and pKM101 strains) and in the absence and presence of induced S9 liver fraction. The five strains are selected to elucidate the base-pair substitution and frameshift mutation generating properties of drug candidates in the early stages of development. The experiments in the absence and presence of the liver fraction serve to test the mutagenicity of the compound itself and its possible metabolites, respectively.

Pharmacokinetics

We analyze the metabolism of the biologically relevant new derivatives by intraperitoneal administration to adult rats followed by HPLC-MS analyses of tissue samples from blood, liver, brain, muscle, heart, lung, kidney and spleen. We also analyze the metabolism of the new compounds with freshly isolated rat hepatocytes also followed by HPLC-MS analyses. We isolate all newly appearing metabolites and determine their structure with MALDI-TOF MS.

Pharmacodynamics

We analyze the metabolism of the biologically relevant new derivatives by intraperitoneal administration to adult rats followed by HPLC-MS analyses of tissue samples from blood, liver, brain, muscle, heart, lung, kidney and spleen. We also analyze the metabolism of the new compounds with freshly isolated rat hepatocytes also followed by HPLC-MS analyses. We isolate all newly appearing metabolites and determine their structure with MALDI-TOF MS.