Piecing together human adult comparative pharmacokinetic trials and rodent studies: What happens to drug clearance in obesity?

In many comparative trials examining the effects of adult obesity on pharmacokinetics of drugs, conclusions were made based on values that were either not adjusted to total body weight or adjusted to non-obese body mass (e.g., ideal or lean body weight). In many cases these values were higher in the obese subjects. We have reviewed the data from comparative human trials, and it is apparent that in examining clearance normalization to total body weight (as typically done in studies involving pediatric obese patients), the clearances are often reduced in the obese. We have also reviewed the results of experimental obese versus non-obese rodent models. Those studies have mostly found that the systemic exposures to the same dose per body weight are increased, with obesity-related decreases in clearance. Furthermore, the expression of a number of important drug metabolizing enzymes are reduced in the experimental obese state. There is also evidence that obesity causes increases in the measured mass of eliminating organs such as liver and kidney. Human clearance normalized to total body weight appears to better reflect the underlying changes reported in the expression of protein and functional activity of drug clearance mechanisms.

Spatiotemporal variation of arbuscular mycorrhizal fungal colonization in olive (Olea europaea L.) roots across a broad mesic-xeric climatic gradient in North Africa.

This study aims to determine the spatiotemporal dynamics of root colonization and spore density of arbuscular mycorrhizal fungi (AMF) in the rhizosphere of olive trees (Olea europaea) with different plantation ages and under different climatic areas in Algeria. Soil and root samples were seasonally collected from three olive plantations of different ages. Other samples were carried out in productive olive orchards cultivated under a climatic gradient (desertic, semi-arid, subhumid, and humid). The olive varieties analysed in this study were Blanquette, Rougette, Chemlel and the wild-olive. Spore density, mycorrhization intensity (M%), spore diversity and the most probable number (MPN) were determined. Both the intensity of mycorrhizal colonization and spore density increased with the increase of seasonal precipitation and decreased with the increase of air temperature regardless of the climatic region or olive variety. The variety Rougette had the highest mycorrhizal levels in all plantation ages and climates. Spore community was composed of the genera Rhizophagus, Funneliformis, Glomus, Septoglomus, Gigaspora, Scutellospora and Entrophospora. The genus Glomus, with four species, predominated in all climate regions. Spores of Gigaspora sp. and Scutellospora sp. were the most abundant in desertic plantations. Statistical models indicated a positive relationship between spore density and M% during spring and winter in young seedlings and old plantations. A significant positive relationship was found between MPN and spore density under different climates. For a mycotrophic species, the rhizosphere of olive trees proved to be poor in mycorrhiza in terms of mycorrhizal colonization and numbers of the infective AMF propagules.

Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2.

Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases.