Effect of organic cosolvent‐induced skeletal muscle damage on the bioavailability of intramuscular [¹⁴C]diazepam

Organic cosolvents are used in many intramuscular formulations for solubilization of drugs and have been shown to cause skeletal muscle damage (myotoxicity). This study explored the influence of organic cosolvent‐induced myotoxicity on the bioavailability of a model compound, diazepam. A tracer (C¹⁴) dose of diazepam was selected which did not elicit any systemic pharmacologic effects (viz., hypothermia and sedation) that might alter the pharmacokinetics of the drug. Male New Zealand White rabbits were injected with diazepam dissolved in three cosolvent:water mixtures (20% v/v propylene glycol, 20% v/v polyethylene glycol 400, and 50% v/v polyethylene glycol 400). These mixtures have similar physicochemical properties, but vary 10‐fold in their in vitro myotoxicity. Using plasma total radioactivity following intramuscular administration of diazepam, statistical differences were not detected in the area under the curve (AUC), the peak concentration, and the time of the observed peak concentration among these treatments, although the in vivo myotoxicity of these systems (measured by the plasma creatine kinase AUC) varied by 10‐fold (p < 0.01). Limited data on unchanged diazepam levels confirmed these observations. Thus, the degree of skeletal muscle damage caused by these organic cosolvent systems does not seem to affect the bioavailability of a tracer dose of intramuscular diazepam.