Tests for Local Toxicity of Intramuscular Drug Preparations: Comparison of in Vivo and in Vitro Methods

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Abstract
Different concentrations of aqueous preparations of metoclopramide, gaboxadol, cis(Z)-clopenthixol digoxin and chlorpromazine and of cis(Z)-clopenthixol acetate in Viscoleo were tested for local toxicity after i.m. injection in rabbits. The weight of macroscopically changed muscle tissue isolated 3 days after injection was determined. In addition, homogenized injection site muscle tissue was analyzed for creatine kinase (CK) activity and by comparison with the CK activity of contralateral muscle tissue, the amount of injection site muscle tissue totally depleted for CK activity was calculated. The substances were also tested for in vitro toxicity. The concentrations of the substances which caused 100% hemolysis of human erythrocytes or minimal cytotoxicity in cell culture assays using MRC-5 fibroblasts were estimated. Metoclopramide and gaboxadol caused no or only minimal local muscle damage in the rabbits. Metoclopramide caused local bleeding. The 4 other substances caused concentration-dependent muscle damage. Although there was some deviations, the 2 in vitro tests reflected reasonably well the in vivo findings. The in vitro tests employed evidently can be useful as screening tests for local toxic effect of i.m. drug preparations. However, further studies are required before conclusion as to predictability can be drawn. The in vitro methods are inexpensive and quick, especially the hemolysis test.