TISSUE DISTRIBUTION OF BUPIVACAINE ENANTIOMERS IN SHEEP

rac-Bupivacaine HCI was infused intravenously to constant arterial blo od 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, th e animal was killed with a bolus of KCl solution, then rapidly dissect ed and samples were obtained from heart, brain, lung, kidney, liver, m uscle, 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 exceede d those of (+)-(R)-bupivacaine by a mean of 29% and this offset the ti ssue:blood distribution coefficients so that the previously significan t enantioselective differences disappeared. It is concluded that altho ugh enantioselectivity of bupivacaine distribution is shown by the mea sured tissue: blood distribution coefficients, it is not shown when ti ssue: plasma water distribution coefficients are calculated, suggestin g that there is no intrinsic difference between the bupivacaine enanti omers in tissue affinity. Sheep given fatal intravenous bolus doses of rac-bupivacaine had significantly greater concentrations of (+)-(R)-b upivacaine than (-)-(S)-bupivacaine in brain (P = 0. 028) and ventricl e (P = 0. 036); these could augment the greater myocardial toxicity of this enantiomer found in vitro. (C) 1993 Wiley-Liss, Inc.