ABSTRACT
The value of cynomolgus and rhesus monkeys to predict human pharmacokinetic parameters has been well established in recent years. However, practical limitations on cost and accessibility can often be a deterrent to obtain data in these valuable species, and the characterization of the predictive power of other nonhuman primates would be useful. Therefore, the present investigation was designed to evaluate the pharmacokinetics of a test set of marketed compounds in the African green monkey, to compare the pharmacokinetics of these agents between nonhuman primate species, and to validate the ability of the African green monkey to predict human pharmacokinetics. Intravenous pharmacokinetics were evaluated for 11 test compounds in this study and compared with data from rats, dogs, cynomolgus/rhesus monkeys, and humans. The results from this investigation indicate that African green monkeys deliver reasonable prediction of human clearance and mean residence time and volume of distribution, although somewhat less accurately than cynomolgus and rhesus monkeys, particularly for volume of distribution, potentially because of body size or composition or experimental design differences. Furthermore, use of an optimized clearance prediction algorithm from the literature enhanced predictivity over a simple liver blood flow-based extrapolation methodology. The data from this study show that African green monkeys have the potential to be used as a surrogate for cynomolgus or rhesus monkeys in preclinical pharmacokinetic studies, particularly for the study of clearance processes, and should be considered as an alternate nonhuman primate test species.
Subject(s)
Chlorocebus aethiops/metabolism , Models, Animal , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/metabolism , Animals , Dogs , Drug Evaluation, Preclinical/methods , Humans , Infusions, Intravenous , Injections, Intravenous , Macaca fascicularis , Macaca mulatta , Male , Pharmacokinetics , Rats , Tissue Distribution/drug effects , Tissue Distribution/physiologyABSTRACT
The Aria LX4 staggered parallel high performance liquid chromatography (HPLC) system is evaluated for application to good laboratory practice (GLP) level quantitative analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS). This system consists of four fully independent binary HPLC pumps, a modified autosampler, and a series of switching and selector valves all controlled by a single computer program. The system improves sample throughput without sacrificing chromatographic separation or data quality. Validation results for four different compounds, each analyzed on a separate channel of the Aria system, show precision and accuracy equivalent to that required of a single-channel system. The results show that sample throughput can be increased nearly four-fold without requiring significant changes in current analytical procedures. The flexibility and ease of use of the Aria system suggest that it should be possible to quickly implement it in any analytical LC/MS/MS environment.
