Thesis-1985-Walmsley.pdf (6.06 MB)
Pharmacokinetics of bumetanide, lorazepam and clofibric acid in cynomolgus monkeys and baboons
thesis
posted on 2012-10-09, 14:05 authored by Lesley WalmsleyThe pharmacokinetics of three unrelated compounds, bumetanide
(a diuretic), lorazepam (an anxiolytic) and clofibric acid (an antihyperlipidaemic
agent), were investigated in two species of non-human
primates commonly used in risk assessment studies. Each of the three
drug substances used was independently administered at each of three
dose levels, the lowest selected to correspond with the human
therapeutic dose (normalised for body weight) and the highest, at ten
times the therapeutic dose, selected to approximate to a dose level
which might be used during chronic toxicity tests. By use of three dose
levels, it was possible to assess whether any non-linear changes in
pharmacokinetics occurred between "pseudo-therapeutic" dose levels
and those likely to be used during risk assessment studies. Two routes
of administration, intravenous and oral, were used at each dose level,
the former to establish the basic pharmacokinetics of each compound,
the latter to assess the absorption characteristics of the drugs and the
systemic availability after oral dosing. Sensitive and specific highperformance
liquid chromatographic assays were developed for the
quantitative measurement of the compounds of interest.
In both the cynomolgus monkey and the baboon, the pharmacokinetics
-1 of bumetanide was linear over the dose range examined (O.03-0.3Omg.kg )
after either intravenous or oral administration. The pharmacokinetics
-1 of lorazepam (dose range O.05-0.50mg.kg ) was also linesr after
intravenous dosing, but the extent of bioavailability after oral
administration was non-linear. The pharmacokinetics of clofibric acid
(dose range 15-150mg.kg-l ) was non-linear (dose-dependent) by either
route of administration.
The pharmacokinetics of the three drug substances in the two
non-human primate species investigsted were compared with published
pharmacokinetic data for these compounds in other animal species,
including man. The use of the non-human primate as a "predictive model"
for the pharmacokinetics of these compounds in humans is considered in
relation to these comparative data and the role of "toxicokinetics" in
the design and interpretation of toxicity studies during safety
evaluation of drugs is discussed.
History
School
- Science
Department
- Chemistry
Publisher
© Lesley WalmsleyPublication date
1985Notes
A Doctoral Thesis submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.Language
- en