Reaction of homopiperazine with endogenous formaldehyde: a carbon hydrogen addition metabolite/product identified in rat urine and blood.

Drug reactivity and bioactivation are of major concern to the development of potential drug candidates in the pharmaceutical industry (Chem Res Toxicol 17:3-16, 2004; Chem Res Toxicol 19:889-893, 2006). Identifying potentially problematic compounds as soon as possible in the discovery process is of great importance, so often early in vitro screening is used to speed up attrition. Identification of reactive moieties is relatively straightforward with appropriate in vitro trapping experiments; however, on occasion unexpected reactive intermediates can be found later during more detailed in vivo studies.

The metabolism of [14C]-zibotentan (ZD4054) in rat, dog and human, the loss of the radiolabel and the identification of an anomalous peak, derived from the animal feed.

This paper presents an overview of a cross-species investigation of the metabolic fate of [(14)C]-zibotentan (ZD4054), with particular focus on the main analytical challenges encountered during the study. A combination of detection methods were used including HPLC coupled to UV, RAD and/or MS(MS), and (1)H NMR spectroscopy. The objective was to characterise and identify the major metabolites found in the circulation and excreta of rat and dog for comparison with those produced in human.

The design of pharmacokinetic studies to support drug discovery: the selection of the optimum number of animals for a study.

Using historic data from development and pre-development compounds, the variability in plasma concentration (including C(max)) and AUC that would be observed when only 1 or 2 animals per time point are used instead of the normal three has been studied. The results indicate that for pharmacokinetic studies carried out during the early discovery phase the number of animals per time point can be reduced to 2 without significantly affecting the quality of the data. Such an approach is not only more efficient, but it conserves valuable compound and reduces by one third the number of animals employed on the study.