Tests for Local Toxicity of Intramuscular Drug Preparations. Comparison of in Vitro and in Vivo Methods
Different concentrations of aqueous preparations of metoclopramide, gaboxadol, cis(Z)-clopenthixol, digoxin and chlorpromazine and of cis(Z)-clopenthixol acetate in Viscoleo have been tested for local toxicity after intramuscular injection in rabbits. The weight of the areas of necrotic muscle tissue isolated 3 days after injection was determined In addition homogenized injection site muscle tissue was analysed for creatine kinase (CK) activity and by comparison with the activity of contralateral muscle tissue, the amount of injection site muscle tissue totally depleted for CK was calculated. The substances have also been 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 local damage in rabbits and this is in agreement with the in vitro results. The four other substances caused concentration dependent muscle damage in the rabbits and there was good correlation between the results from the in vitro methods. Although there were some discrepancies, the two in vitro tests predicted, reasonably well, the in vivo finding.
The results of this preliminary study suggest that the in vitro tests employed seem to be useful as screening tests for local toxicity of intramuscular drug preparations. However, further studies are required before any conclusion, as to predictability, can be drawn. The in vitro methods are inexpensive and quick, especially the hemolysis test. If a substance causes hemolysis or cytotoxicity in low concentrations, it is recommended that the result be confirmed in vivo.
Key wordsIntramuscular injection Local toxicity Creatine kinase Rabbits Cell culture Hemolysis
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