Disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments in rats.
BACKGROUND
This study was designed to determine the disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments, using multiple sampling time points in chronically prepared awake pregnant rats.


METHODS
All animals received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 h after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry.


RESULTS
The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefold higher in the maternal and 11-fold higher than in the fetal plasma. At 4 h after dosing, bupivacaine was no longer detectable in any maternal and fetal samples, whereas 3'-hydroxybupivacaine was still present in all tissues except the fetal plasma and heart.


CONCLUSIONS
These data indicate that a considerable amount of bupivacaine is taken up by both sides of the placenta, as well as the amnion and myometrium. 3'-Hydroxybupivacaine was present in all tissues except the fetal plasma and heart samples, even after the parent compound became no longer detectable. Whether this slow elimination of 3'-hydroxybupivacaine causes any adverse effects on the fetus-newborn needs to be explored.
Morishima
H O
HO
Departments of Anesthesiology and Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA. hom2@columbia.edu
Ishizaki
A
A
Zhang
Y
Y
Whittington
R A
RA
Suckow
R F
RF
Cooper
T B
TB
D000650:Amnion / Q000378:metabolism; D000779:Anesthetics, Local / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002045:Bupivacaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D009215:Myometrium / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
C121551:3-hydroxybupivacaine; D000779:Anesthetics, Local; D002045:Bupivacaine