TOXICITY OF BUPIVACAINE AND ROPIVACAINE IN RELATION TO FREE PLASMA-CONCENTRATIONS IN PREGNANT RATS - A COMPARATIVE-STUDY

The relationship between free drug concentration and toxicity of bupiv acaine and ropivacaine, a new local anaesthetic agent, was studied in a pregnant rat model. The compounds were given subcutaneously to rats in late pregnancy. Dose levels (bupivacaine 5.5 to 24 mg/kg and ropiva caine 5.3 to 26 mg/kg) were selected based upon the proposed human dos age and the known pharmacological activity of the compounds. Chewing, spasm, dyspnoea, drowsiness, salivation and convulsions were observed in a dose-dependent manner in the animals given 14 to 24 mg/kg of bupi vacaine, while only a few animals receiving 26 mg/kg of ropivacaine sh owed less severe symptoms. Deaths from clonic convulsions were occasio nally seen in animals receiving 14 mg/kg or more of bupivacaine. No an imals receiving ropivacaine died. No effects on litter size, offspring loss or weight of the offspring at birth were observed with one excep tion. After 24 mg/kg of bupivacaine an increased postnatal loss of the offsprings were noticed, most likely due to impaired maternal care. P rotein binding, at expected C-max, were significantly lower for ropiva caine (around 49%) compared with bupivacaine (around 69%) at dose leve ls. The results suggest an increased safety margin before onset of tox ic side effects after treatment with ropivacaine, compared to bupivaca ine, in pregnant rase.