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Ontogeny of drug disposition in the newborn : studies examining valproic acid and diphenhydramine in chronically instrumented lambs Wong, Harvey


Valproic acid (VPA, a low clearance carboxylic acid) and diphenhydramine (DPHM, a high clearance amine) were investigated in chronically instrumented lambs to examine developmental changes in their pharmacokinetics and metabolism. In 10 day old, 1 month old and 2 month old lambs, and adult sheep, VPA clearance followed a pattern similar to humans. With a 10 mg/kg VPA i.v. bolus, both unbound and total VPA clearance increased significantly up to 2 months of age before decreasing to adult levels. Plasma protein binding was nonlinear in all ages examined with the area weighted unbound fraction being significantly higher in 10 day old lambs. A substantial (~2.5 fold) increase in urinary recovery of VPA-glucuronide in 2 month old lambs in comparison to 10 day old lambs suggested that changes in clearance may be largely related to post-natal development of enzymes involved in VPA glucuronidation. Finally, as with other organic acids, VPA renal clearance was initially low and increased with age. In a subsequent dose-ranging experiment in 10 day old lambs and adult sheep, the lambs appeared to have a lower binding capacity, but a higher binding affinity for VPA than adult sheep. Metabolic capacity was similar in 10 day old and adult sheep, however, the apparent in vivo K[sub m] was lower in the adult. Differences in K[sub m] appeared to account for the observed dose-dependent changes in unbound clearance for the two age groups. Estimates of apparent in vivo V[sub max]and K[sub m] appeared to largely reflect developmental differences in VPA glucuronidation.

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