Pharmacokinetics of bumetanide, lorazepam and clofibric acid in cynomolgus monkeys and baboons
2012-10-09T14:05:07Z (GMT) by
The 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.