Item – Theses Canada

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OCLC number
46496187
Author
Gordon, John David,1965-
Title
Pharmacokinetics, metabolism, placental transfer and fetal effects of valproic acid in pregnant sheep.
Degree
Ph. D. -- University of British Columbia, 1995
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, 1996.
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
The purpose of these studies was to assess the pharmacokinetics, metabolism and fetal effects of valproic acid (VPA) in pregnant sheep. Following i.v. bolus administration, the disposition of VPA was best described by a biexponential function with a t$\sb{1/2\beta}$ of 2.13 $\pm$ 0.49 h in maternal serum and 3.37 $\pm$ 1.37 h in fetal serum. The total body clearances (CL$\rm\sb{T}$) for the ewe and fetus were 0.083 $\pm$ 0.027 Lh$\rm\sp{-1}kg\sp{-1}$ and 0.529 $\pm$ 0.306 Lh$\rm\sp{-1}kg\sp{-1}$, respectively. Significant fetal exposure to VPA was observed following maternal dosing (AUC$\rm\sb{\infty FA}$/AUC$\rm\sb{\infty MA}$ of 0.410 $\pm$ 0.118). VPA appeared rapidly in amniotic and fetal tracheal fluids but did not accumulate extensively in either. 11 VPA metabolites were detected following i.v. bolus dosing. The metabolite levels in maternal serum were consistently higher than fetal levels irrespective of the site of drug administration. Simultaneous i.v. infusion studies were also performed achieving steady-state concentration ratios of VPA and ($\rm\sp{13}C\sb4$) VPA in fetal serum to that in maternal serum (i.e., C$\rm\sb{{f}\sb{ss}}$/C$\rm\sb{{m}\sb{ss}}$) of 0.55 $\pm$ 0.11 and 1.90 $\pm$ 0.38, respectively. Maternal (CL$\rm\sb{m}$) and fetal (CL$\rm\sb{f}$) total body clearances were 3.6 $\pm$ 0.9 mL min$\sp{-1}$ kg$\sp{-1}$ maternal weight and 63.0 $\pm$ 22.8 mL min$\rm\sp{-1}kg\sp{-1}$ fetal weight. Of these values, the maternal nonplacental clearance contributed approximately 69% of the CL$\rm\sb{m}$ while the fetal nonplacental clearance (CL$\rm\sb{fo}$) apparently made no contribution to CL$\rm\sb{f}$. The maternal renal clearance, 0.521 $\pm$ 0.071 mL min$\rm\sp{-1}kg\sp{-1}$ maternal weight, accounts for approximately 20% of the total maternal nonplacental clearance (CL$\rm\sb{mo}$). In contrast, there was essentially no renal excretion of VPA from the fetus. Metabolite data suggests that ($\rm\sp{13}C\sb4$) VPA undergoes transfer to the ewe followed by metabolism, with the resulting labelled metabolites being transferred back to the fetus. This data further supports the apparent lack of fetal nonplacental clearance of VPA. The most significant physiological effect of the administration of VPA was a decrease in fetal breathing activity although other transient cardiovascular effects were noted in the infusion studies.
ISBN
0612059677
9780612059672