A sensitive method for the measurement of the novel pet endectocide, selamectin (UK-124,114), in dog and cat plasma by chemical derivatisation and high-performance liquid chromatography with fluorescence detection.

An analytical method has been developed for the novel pet endectocide, selamectin (USAN, UK-124, 114), in dog and cat plasma to facilitate pharmacokinetic profiling for this compound. The method involves solid phase extraction of the compound and internal standard from plasma followed by chemical derivatisation using triethylamine and trifluoroacetic anhydride. This reaction yields a highly fluorescent product and thus provides a sensitive assay. Using a sample volume of 1.0 ml for dog plasma the assay has been validated over a concentration range of 0.2-40 ng/ml. Due to smaller plasma volumes for cat plasma samples, the assay was validated over a concentration range of 1.0- 200 ng/ml using a sample volume of 0.2 ml. The analyte has been shown to be stable for 48 h at room temperature and through three freeze thaw cycles in dog plasma. The analytical method is highly specific and proved suitable for the analysis of selamectin in dog and cat plasma samples following doses of compound by parenteral and non-parenteral routes.

Long-range transport and global fractionation of POPs: insights from multimedia modeling studies.

The long-range transport of persistent organic pollutants (POPs) is investigated with two multimedia box models of the global system. ChemRange is a purely evaluative, one-dimensional steady-state (level III) model; CliMoChem is a two-dimensional model with different temperatures, land/water ratios and vegetation types in different latitudinal zones. Model results are presented for three case studies: (i) the effect of atmospheric aerosol particles on the long-range transport of POPs, (ii) the effect of oceanic deposition on the long-range transport of different PCB congeners, (iii) the global fractionation of different PCB congeners. The model results for these case studies show: (i) the low atmospheric half-lives estimated for several organochlorine pesticides are likely to be inconsistent with the observed long-range transport of these compounds; (ii) export to the deep sea reduces the potential for long-range transport of highly hydrophobic compounds (but does not remove these chemicals from the biosphere); (iii) there are different meanings of the term global fractionation that refer to different aspects of the fractionation process and need to be distinguished. The case-study results further indicate that the influences of varying environmental conditions on the physicochemical properties and the degradation rate constants of POPs need to be determined.

Introducing integrated product and process development into the education of science and engineering undergraduates: a lecture course with an accompanying case-study programme at the ETH chemistry department.

Increased quality requirements in the development of chemical products and a growing awareness within society of the activities of chemical companies present a new challenge to the education of young scientists. Nowadays, the teaching of chemists, chemical engineers and environmental scientists at universities has to go beyond the traditional, discipline-orientated knowledge acquisition. The students also have to learn to work and communicate in interdisciplinary teams, to solve application-oriented tasks and to integrate scientific, economical, ecological and social aspects into their work. For this reason, a case-study programme was launched at the chemistry department of the Swiss Federal Institute of Technology. In this paper, we describe the organisational aspects of the programme, its inclusion into academic and industrial environments and summarise some of the scientific methodologies applied. One of the seven case-studies, an assessment of a modern insecticide, is presented in more detail. Finally, we discuss how far the case-study programme is suitable for introducing a new mode of knowledge production to universities.

Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver.

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.

Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.

The use of statins is widespread across disease areas because many patients have comorbidities. Given that these drugs have become common as comedications, it is essential to have an understanding of the potential risks of drug-drug interactions (DDIs) between statins and candidate drugs in development. Although the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1) is known to play a substantial role in statin-related DDI risk, other transporters and metabolizing enzymes can also be involved. Consequently, a holistic approach to risk assessment is required, tailored to each statin. Using evidence from pharmacogenetics, DDIs, and literature on absorption, distribution, metabolism, and elimination (ADME) in humans, this review identifies pathways that contribute the most to, and are therefore the most critical to, the disposition of each statin. It also provides an understanding of the expected theoretical maximum increase in systemic exposure if the disposition of a statin is inhibited. Finally, on a statin-by-statin basis, we propose in vitro inhibition studies that should be routinely conducted during drug development so as to better assess DDI risk.

Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug.

The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).

Unionization: boon or bane?

Again, you only get a union if you deserve one, and you get the union you deserve. Collective bargaining in a professional milieu indicates an unhealthy environment, is incredibly cumbersome, and--perhaps most concerning--is phenomenally expensive, as measured in terms of fiscal resources, human resources, and energies. Moreover, time lost in collective bargaining reduces institutional flexibility and responsiveness. But more important, the collective bargaining process imposes an additional administrative layer and extra legal and contract implementation fees and adds mistrust into a professional setting that requires total trust along with professional competence. Thus, resources are diverted that could be better devoted to excellent patient care and professional salaries. The process of maintaining a union-free environment is well worth the effort. In the end, administration, nursing personnel, and, most important, patient care are positively impacted by an open, flexible environment. In short, within a healthy union-free environment, everyone wins!

Absorption, distribution, metabolism, and excretion considerations in selection of orally active indole-containing endothelin antagonist.

A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. Early compounds in this series were found to show poor gastrointestinal absorption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding potential, through a reduction in the number of H-bond donors and acceptors, could increase absorption of the molecules. There was a correlation between calculated H-bonding capacity and rate of permeability across Caco-2 monolayers for this series of compounds. Caco-2 permeability was also shown to be indicative of the estimated extent of absorption in rats. Balancing the requirements of absorption and systemic clearance lead to the selection of an alcohol-containing compound, compound 7a (single enantiomer of compound 7) that was moderately absorbed after oral administration and converted to an active acid metabolite, which itself was of low intrinsic clearance. Species differences were observed between the absorption of compound 7a in rat and dog and also in the extent of conversion to the acid metabolite. Absorption was estimated at 30% in rat and 100% in dog. Approximately 30% of the absorbed drug was converted to systemically available acid metabolite in rat, compared with only 3% in dog.