Abstract
Separate 24-h maternal and fetal infusions of valproic acid (VPA) were administered to five pregnant sheep at 125 to 138 days gestation (term ∼145 days) to determine maternal-fetal disposition. The pharmacokinetics of VPA were also investigated in five newborn 1-day-old lambs after a 6-h drug infusion. Plasma, urine, and amniotic and fetal tracheal fluid samples were analyzed for VPA using gas chromatography-mass spectrometry. During maternal drug infusion, the average steady-state fetal/maternal unbound VPA plasma concentration ratio was 0.81 ± 0.09. Unbound maternal-to-fetal VPA placental clearance (69.0 ± 20.2 ml/min/kg) was similar to that in the other direction (61.9 ± 24.2 ml/min/kg); this indicates passive placental diffusion and intermediate placental permeability of VPA in sheep. Newborn unbound VPA clearance (0.66 ± 0.28 ml/min/kg) was much lower than in the mother (5.4 ± 2.7 ml/min/kg) or the fetus (62.1 ± 22.4 ml/min/kg), and exhibited pronounced Michaelis-Menten characteristics. The elimination half-life of the drug was much longer in the newborn (18.6 ± 2.6 h) relative to the mother (5.6 ± 1.4 h) and the fetus (4.6 ± 1.9 h). Thus, VPA elimination in newborn lambs is much slower as compared with adult sheep, a situation similar to that in humans. Plasma protein binding of VPA was saturable, with similar VPA binding capacities and affinities in maternal and fetal plasma. VPA was extensively displaced from binding sites in the newborn lamb during the first 1 to 2 days of life, possibly because of increased plasma free fatty acid concentrations at birth. Thereafter, newborn plasma appeared to have a similar VPA binding capacity but lower affinity compared with the mother and the fetus.
Footnotes
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Send reprint requests to: Dr. Dan W. Rurak, B.C. Research Institute for Children's and Women's Health, 950 West 28th Ave., Vancouver, British Columbia, Canada V5Z 4H4. E-mail:drurak{at}cw.bc.ca
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These studies were supported by funding from the Medical Research Council of Canada. S.K. was the recipient of a University of British Columbia Graduate Fellowship. H.W. is supported by a Pharmaceutical Manufacturers of Canada/Medical Research Council studentship. D.W.R. is the recipient of an Investigatorship award from the British Columbia Children's Hospital Foundation.
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1 A part of this work was presented at the 5th International Meeting of the International Society for the Study of Xenobiotics Meeting and is abstracted in ISSX Proc(1998) 13:73.
- Abbreviations used are::
- VPA
- valproic acid
- AIC
- Akaike's Information Criterion
- AUC
- area under the curve of arterial plasma concentration-time profile
- AUMC
- area under the first-moment curve
- CLm(net)
- net maternal clearance of the total drug
- CLmm
- maternal total clearance of the total drug
- CLmf
- maternal-to-fetal placental clearance of the total drug
- CLmo
- maternal nonplacental clearance of the total drug
- CLf(net)
- net fetal clearance of the total drug
- CLff
- fetal total clearance of the total drug
- CLfm
- fetal-to-maternal placental clearance of the total drug
- CLfo
- fetal nonplacental clearance of the total drug
- CLtb
- total body clearance
- Cm
- maternal plasma steady-state concentration after maternal drug administration
- Cf
- fetal plasma steady-state concentration after maternal drug administration
- Cm′
- maternal plasma steady-state concentration after fetal drug administration
- Cf′
- fetal plasma steady-state concentration after fetal drug administration
- MRT
- mean residence time
- t1/2β
- terminal elimination half-life
- t1/2uβ
- unbound drug
- Vdss
- steady-state volume of distribution
- Received September 2, 1999.
- Accepted April 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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