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Ontogeny of drug disposition in the newborn : studies examining valproic acid and diphenhydramine in chronically instrumented lambs Wong, Harvey
Abstract
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.
Item Metadata
Title |
Ontogeny of drug disposition in the newborn : studies examining valproic acid and diphenhydramine in chronically instrumented lambs
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2000
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Description |
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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Extent |
7057103 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-07-23
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0089708
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2000-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.