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

  • Fl. Højelse
  • O. Svendsen
  • R. E. Bagdon
Conference paper
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 8)


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 words

Intramuscular injection Local toxicity Creatine kinase Rabbits Cell culture Hemolysis 


  1. Bagdon RE, Prince HN (1983) Assessment of primary irritation of parenteral drugs in vitro. 24th Congress of the European Society of Toxicology, abstract p. 93.Google Scholar
  2. Diness V (1982) Bestemmelse af injektionsskader ved kreatinkinase-(CK-) metoden efter intramuskulaer injection af laegemidler til kaniner og svin. (Determination of injection-site injury by creatine kinase (CK) method after intramuscular injection of drugs in rabbits and pigs.) Ph. D. Thesis, Copenhagen.Google Scholar
  3. Oshida S, Degawa K, Takahashi Y, Akaishi S (1979) Physicochemical properties and local toxic effects of injectables. Tohoku J Exp Med 127: 301–316PubMedCrossRefGoogle Scholar
  4. Steiness E, Rasmussen F, Svendsen O, Nielsen P (1978) A comparative study of serum creatine phosphokinase ( CPK) activity in rabbits, pigs and humans after intramuscular injection of local damaging drugs. Acta Pharmacol Toxicol 42: 357–364Google Scholar
  5. Svendsen O (1983) Local muscle damage and oily vehicles. A study on local reactions in rabbits after intramuscular injection of neuroleptic drugs in aqueous or oily vehicles. Acta Pharmacol Toxicol 52: 298–304CrossRefGoogle Scholar
  6. Svendsen O, Rasmussen F, Nielsen P, Steiness F (1979) The loss of creatine phosphokinase (CK) from intramuscular injection sites in rabbits. A predictive tool for local toxicity. Acta Pharmacol Toxicol 44: 324–328Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • Fl. Højelse
    • 1
  • O. Svendsen
    • 1
  • R. E. Bagdon
    • 2
  1. 1.Department of Pharmacology and ToxicologyH. Lundbeck A/SCopenhagen-ValbyDenmark
  2. 2.Robert Edward Bagdon, Inc.LivingstonUSA

Personalised recommendations