Transplacental and nonplacental clearances, metabolism and pharmacodynamics of labetalol in the fetal lamb after direct intravenous administration.
Labetalol has been previously shown to cause significant maternal and fetal metabolic effects in pregnant sheep after maternal administration. To investigate these observations further, the present study describes the pharmacokinetics, metabolism and pharmacodynamics of labetalol in the fetal lamb after direct fetal i.v. bolus (4 mg) administration. The fetal total body clearance of labetalol (50.45 +/- 1.37 ml m-1 kg-1), which was significantly higher than that previously determined in the ewe, was composed of transplacental and nonplacental CLs of 23.4 +/- 8.99 ml m-1 kg-1 and 27.05 +/- 10.36 ml m-1 kg-1, respectively. The maternal to fetal plasma labetalol area under the curve ratio was 0.031 +/- 0.002 and the CLmp and CLmn were 7.27 +/- 2.11 ml m-1 kg-1 and 30.5 +/- 5.94 ml m-1 kg-1, respectively. Labetalol concentrations in fetal tracheal fluid were consistently higher than that in fetal plasma. The glucuronide conjugate of labetalol was found in the amniotic fluid at up to 20 times the free drug concentration but the oxidative metabolite, 3-amino-1-phenyl-butane, was not detected in plasma or amniotic fluid samples. The fetal effect of labetalol was characterized by an acute lactic acidosis. The calculated hind limb arteriovenous lactate flux showed a net output of lactic acid equal to 3.85 +/- 2.05 g from the hind limb over 24 h after labetalol administration. Although the fetal exposure to labetalol in this study was roughly 4 times that after a 100-mg maternal bolus administration, the magnitude of fetal lactic acidosis was not significantly different in these studies. The clinical implications of the observations made in this study remain to be investigated.
Yeleswaram
K
K
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Rurak
D W
DW
Kwan
E
E
Hall
C
C
Doroudian
A
A
Wright
M R
MR
Abbott
F S
FS
Axelson
J E
JE
D000818:Animals; D001784:Blood Gas Analysis; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D007741:Labetalol / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D007773:Lactates / Q000097:blood; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep
D007773:Lactates; D007741:Labetalol