Cationic drug pharmacokinetics in diseased livers determined by fibrosis index, hepatic protein content, microsomal activity, and nature of drug

The disposition kinetics of six cationic drugs in perfused diseased and normal rat livers were determined by multiple indicator dilution and related to the drug physicochemical properties and liver histopathology. A carbon tetrachloride (CCl4)induced acute hepatocellular injury model had a higher fibrosis index (FI), determined by computer-assisted image analysis, than did an alcohol-induced chronic hepatocellular injury model. The alcohol-treated group had the highest hepatic alpha(1)- acid glycoprotein, microsomal protein (MP), and cytochrome P450 (P450) concentrations. Various pharmacokinetic parameters could be related to the octanol-water partition coefficient (log P-app) of the drug as a surrogate for plasma membrane partition coefficient and affinity for MP or P450, the dependence being lower in the CCl4-treated group and higher in the alcohol-treated group relative to controls. Stepwise regression analysis showed that hepatic extraction ratio, permeability-surface area product, tissue-binding constant, intrinsic clearance, partition ratio of influx (k(in)) and efflux rate constant (k(out)), and k(in)/k(out) were related to physicochemical properties of drug (log P-app or pK(a)) and liver histopathology (FI, MP, or P450). In addition, hepatocyte organelle ion trapping of cationic drugs was evident in all groups. It is concluded that fibrosis-inducing hepatic disease effects on cationic drug disposition in the liver may be predicted from drug properties and liver histopathology.

A molecular phylogeny of the Australian skink genera Eulamprus, Gnypetoscincus and Nangura

Skinks from the genera Eulamprus, Gnypetoscincus and Nangura are a prominent component of the reptile fauna of the mesic forests of the east coast of Australia and have been the subject of numerous ecological studies. Highly conserved morphology and the retention of ancestral traits have limited our understanding of the relationships within and among these genera beyond an initial identification of species groups within Eulamprus. To address this deficit and to explore the relationships between Eulamprus and the monotypic genera Nangura and Gnypetoscincus, sections of two mitochondrial genes (ND4 and 16S rRNA) were sequenced and subjected to Bayesian phylogenetic analysis. This phylogenetic analysis supports recognition of the three species groups proposed for Eulamprus (murrayi, quoyii and tenuis) and indicates that this genus is paraphyletic, with Gnypetoscincus and Nangura being proximal to basal lineages of the tenuis group. To resolve these and broader problems of paraphyly, we suggest that each of the species groups from 'Eulamprus' should be recognised as a distinct genus. The phylogenetically and ecologically distinct water skinks of the quoyii group would be retained within Eulamprus and the diverse species of the tenuis group allocated to Concinnia. We suggest placing the monophyletic murrayi group, endemic to the rainforests of central eastern Australia, in a new genus ( yet to be formally described). The sequencing data also revealed the existence of a genetically divergent but morphologically cryptic lineage within E. murrayi and substantial diversity within E. quoyii. There is evidence for two major habitat shifts from rainforest towards drier habitats, one leading to the quoyii group and the second defining a clade of three species within the tenuis complex. These ecological transitions may represent adaptations to general drying across eastern Australia during the late Miocene - Pliocene. Each of the major areas of east coast tropical or subtropical rainforest contains multiple phylogenetically diverse endemic species, reflecting the long-term persistence and high conservation value of wet forest habitats in each area.