Tissue distribution of bupivacaine enantiomers in sheep.
rac-Bupivacaine HCl was infused intravenously to constant arterial blood drug concentrations in sheep using a regimen of 4 mg/min for 15 min followed by 1 mg/min to 24 h. At 24 h, arterial blood was sampled, the animal was killed with a bolus of KCl solution, then rapidly dissected and samples were obtained from heart, brain, lung, kidney, liver, muscle, fat, gut, and rumen. Tissue:blood distribution coefficients for (+)-(R)-bupivacaine exceeded those of (-)-(S)-bupivacaine (P < 0.05) for heart, brain, lung, fat, gut, and rumen by an overall mean of 43%. Blood:plasma distribution coefficients of (-)-(S)-bupivacaine exceeded those of (+)-(R)-bupivacaine by a mean of 29% and this offset the tissue:blood distribution coefficients so that the previously significant enantioselective differences disappeared. It is concluded that although enantioselectivity of bupivacaine distribution is shown by the measured tissue:blood distribution coefficients, it is not shown when tissue:plasma water distribution coefficients are calculated, suggesting that there is no intrinsic difference between the bupivacaine enantiomers in tissue affinity. Sheep given fatal intravenous bolus doses of rac-bupivacaine had significantly greater concentrations of (+)-(R)-bupivacaine than (-)-(S)-bupivacaine in brain (P = 0.028) and ventricle (P = 0.036); these could augment the greater myocardial toxicity of this enantiomer found in vitro.
Rutten
A J
AJ
Department of Anaesthesia and Intensive Care, Flinders Medical Centre, Adelaide, Australia.
Mather
L E
LE
McLean
C F
CF
Nancarrow
C
C
D000818:Animals; D001921:Brain / Q000378:metabolism; D002045:Bupivacaine / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D007262:Infusions, Intravenous; D009206:Myocardium / Q000378:metabolism; D012756:Sheep; D013237:Stereoisomerism; D014018:Tissue Distribution
D002045:Bupivacaine