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 bupivacaine 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 ropivacaine 5.3 to 26 mg/kg) were selected based upon the proposed human dosage 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 bupivacaine, while only a few animals receiving 26 mg/kg of ropivacaine showed less severe symptoms. Deaths from clonic convulsions were occasionally seen in animals receiving 14 mg/kg or more of bupivacaine. No animals receiving ropivacaine died. No effects on litter size offspring loss or weight of the offspring at birth were observed with one exception. After 24 mg/kg of bupivacaine an increased postnatal loss of the offsprings were noticed, most likely due to impaired maternal care. Protein binding, at expected Cmax, were significantly lower for ropivacaine (around 49%) compared with bupivacaine (around 69%) at dose levels. The results suggest an increased safety margin before onset of toxic side effects after treatment with ropivacaine, compared to bupivacaine, in pregnant rase.
Danielsson
B R
BR
Laboratory of Safety Assessment, Astra AB, Södertälje, Sweden.
Danielson
M K
MK
Böö
E L
EL
Arvidsson
T
T
Halldin
M M
MM
D000577:Amides / Q000097:blood / Q000633:toxicity*; D000779:Anesthetics, Local / Q000097:blood / Q000633:toxicity*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002045:Bupivacaine / Q000097:blood / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007279:Injections, Subcutaneous; D008297:Male; D010865:Pilot Projects; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000187:drug effects*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077212:Ropivacaine
D000577:Amides; D000779:Anesthetics, Local; D000077212:Ropivacaine; D002045:Bupivacaine