The myotoxicity of organic cosolvents following intramuscular injection: Characterization and mechanistic studies
An in vitro rat muscle model for myotoxicity estimation was first developed. This system, which utilizes creatine kinase release as an index of myotoxicity, allows the myotoxicity of intramuscular solutions to be rapidly screened, without the limitations associated with published methods. This in vitro myotoxicity screening technique was validated against in vivo myotoxicity data in rabbits. The concentration-myotoxicity relationships were determined for the aqueous solutions of each of the cosolvents. The myotoxicity of mixed solvents consisting of propylene glycol, ethanol, and water was shown to be additive. This relationship of linear combination did not apply to ternary mixtures containing polyethylene glycol 400, which appeared to exert a protective effect in these mixtures. The possible mechanisms of organic cosolvent-induced myotoxicity were investigated. Myotoxicity was shown not to be linearly correlated with simple physicochemical properties nor with linear combinations of these properties. Results from biochemical studies suggested that organic cosolvent-induced creatine kinase release was caused by alterations in intracellular calcium homeostasis and not by direct solubilization of the sarcolemma. A final study explored the effect of muscle damage on the intramuscular bioavailability of a model compound dissolved in three cosolvent solutions with similar physicochemical properties but with different myotoxicities. Relative-bioavailability of a {sup 14}C-diazepam tracer dose was not different among these solutions, while the in vivo myotoxicity of the solutions varied ten fold. These initial findings suggest that intramuscular drug bioavailability does not appear to be affected by skeletal muscle damage.
- Research Organization:
- New York Univ., NY (United States)
- OSTI ID:
- 5542823
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKALINE EARTH METALS
ANIMALS
BIOLOGICAL AVAILABILITY
BIOLOGICAL MODELS
CALCIUM
CARBON 14 COMPOUNDS
CARBON COMPOUNDS
DISPERSIONS
ELEMENTS
ENZYMES
HOMEOSTASIS
INJECTION
INTAKE
INTRAMUSCULAR INJECTION
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
METABOLISM
METALS
MIXTURES
ORGANIC SOLVENTS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
RATS
RODENTS
SECRETION
SOLVENTS
TOXICITY
TRACER TECHNIQUES
TRANSFERASES
VERTEBRATES