New approaches for drug and kinetic analysis in the maternal-fetal unit.
The development of more sensitive and selective analytical techniques has greatly improved scientists' ability to study the PK, PD, and metabolism of drugs in pregnancy. This chapter has chronicled the evolution of the study of drug disposition in pregnant sheep in the laboratory. With the advent of more sensitive and selective analytical techniques, researchers have been able to progress significantly beyond measuring the extent of fetal drug exposure by a single-point determination. A number of interesting and significant advances have been made using highly selective and specific analytical techniques (i.e., gas chromatography-electron-capture detection, gas chromatography-nitrogen phosphoros-specific detection, and gas chromatography-mass spectroscopy). Researchers have characterized drug kinetics in multiple fluids from the pregnant sheep (amniotic fluid, fetal and maternal plasma and urine, and fetal tracheal fluid) and have demonstrated extensive accumulation of several basic drugs in the fluid produced by the fetal lung. With the simultaneous administration of labeled and unlabeled drug to the ewe and fetus researchers have, for the first time, examined the assumption that the clearance parameters determined from the model developed by Szeto and coworkers (1982) are not affected by the time interval between maternal and fetal infusions given on separate days. Also using SIL drug, researchers have characterized fetal hepatic first-pass drug clearance in a chronic preparation. With the establishment of a stereoselective assay for labetalol, scientists have begun to examine the fetal exposure to the individual enantiomers of racemic drugs in pregnancy. The availability of newer analytical tools and techniques (i.e., HPLC interfaced with tandem mass spectrometers) will further expand the study of drugs in pregnancy and challenge the creativity of future investigators in this field.
Tonn
G R
GR
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Doroudian
A
A
Gordon
J G
JG
Rurak
D W
DW
Riggs
K W
KW
Abbott
F S
FS
Axelson
J E
JE
D000818:Animals; D004155:Diphenhydramine / Q000493:pharmacokinetics; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007741:Labetalol / Q000493:pharmacokinetics; D008787:Metoclopramide / Q000493:pharmacokinetics; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D012756:Sheep; D013237:Stereoisomerism; D014635:Valproic Acid / Q000493:pharmacokinetics
D014635:Valproic Acid; D004155:Diphenhydramine; D008787:Metoclopramide; D007741:Labetalol