Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice

The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol. Its oral bioavailability is very low due to the action of P-glycoprotein in the gut wall and CYP450 in gut wall and liver. However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed. We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF’s) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF’s without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself. Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor EL-ethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF’s maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels

Chromatin compaction in terminally differentiated avian blood cells: the role of linker histone H5 and non-histone protein MENT

Chromatin has a tendency to shift from a relatively decondensed (active) to condensed (inactive) state during cell differentiation due to interactions of specific architectural and/or regulatory proteins with DNA. A promotion of chromatin folding in terminally differentiated avian blood cells requires the presence of either histone H5 in erythrocytes or non-histone protein, myeloid and erythroid nuclear termination stage-specific protein (MENT), in white blood cells (lymphocytes and granulocytes). These highly abundant proteins assist in folding of nucleosome arrays and self-association of chromatin fibers into compacted chromatin structures. Here, we briefly review structural aspects and molecular mode of action by which these unrelated proteins can spread condensed chromatin to form inactivated regions in the genome

Primary exposure and effects in non-target animals

The toxicity of anticoagulant rodenticides to non-target species is one of the root concerns over wide-scale use of these compounds. Compared with the numerous studies documenting secondary exposure in predators, there have been relatively few studies on primary exposure in non-targets. We consider why primary exposure of non-targets occurs, which species are most likely to be exposed, how and why exposure magnitude varies, and whether exposure results in ecologically significant effects. Species groups or trophic guilds most at risk of primary exposure include invertebrates, reptiles, birds and mammals. Relatively little is known about exposure and particularly effects in invertebrates and reptiles although recent studies suggest that anticoagulants may impact invertebrates, presumably through different toxic pathways to those that result in vertebrate toxicity. Amongst higher vertebrates, primary exposure occurs in some bird species but there is little information on extent and importance. There are more studies on non-target mammals and it is granivorous species that are most likely to feed on bait and accumulate residues, as might be predicted given their ecological and trophic similarities to target species. However, studies suggest a surprisingly high degree of exposure in shrews, although it is unclear the extent to which this is primary and/or secondary. Overall, arguably the most striking aspect of primary exposure in mammals is the large-scale variation both in the proportion of animals exposed and the magnitude of residues accumulated. We consider the multiple abiotic and biotic factors that may drive this, including the direct and indirect effects of resistance in target species. In terms of ecologically significant effects, primary exposure clearly does cause acute mortalities in non-target vertebrates and these have been associated with significant population impacts on intensively baited islands where there has been limited or no potential for immigration. Localised population impacts have also been documented in mainland small mammals but most non-targets are likely to be r-selected species. Population declines may therefore be expected to be relatively short-term, provided baiting is episodic, as population numbers can recover through high intrinsic rate of reproduction in survivors, reduced density-dependent mortality, and immigration. However, prolonged or permanent baiting may potentially result in long-term depletion of resident non-target populations that is ameliorated only by immigration; such areas may act as population sinks