Diurnal changes in capecitabine clock-controlled metabolism enzymes are responsible for its pharmacokinetics in male mice

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5 '-deoxy-5-fluorocytidine (5 ' DFCR), 5 '-deoxy-5-fluorouridine (5 ' DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma C-max and AUC(0-6h) (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5 ' DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, C-max and AUC(0-6h) values of 5 ' DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5 ' DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.Istanbul Universit

Active tectonics of the Izmit Gulf (NE Marmara Sea): from high resolution seismic and multi-beam bathymetry data

Several active faults were determined in the Gulf of Izmit, using high-resolution shallow seismic and multi-beam bathymetry data. One of them is a buried fault (Fault 2), following central axis of the gulf which forms the current morphology within its releasing and restraining bends. Releasing bends control the current morphology of the sub-basins. Also restraining bends form folds in the central basin and a thrust in the western basin. A left step over between two strike-slip faults (Faults 2 and II) creates a transpressional area. Therefore, Hersek and Catal deltas are uplifted

A detailed study on the chemical and biological profiles of essential oil and methanol extract of Thymus nummularius (Anzer tea): Rosmarinic acid

The aim of this study was to determine the chemical profile of Thymus nummularius by LC-MS/MS and GC/MS. Additionally, the methanol extract, essential oil and some individual main compounds of Thymus nummularius were tested for antioxidant, anticholinesterase and antimicrobial activities. Besides, HPLC-FLD was used to determine total aflatoxin in the plant material. Among the twenty-seven compounds studied by LC-MS/MS, rosmarinic acid (131,898.9 +/- 6463.0 mu g/g dry-extract) was found to be the most abundant compound in the methanol extract. On the other hand, thymol (60.38%) and terpinyl-acetate (10.49%) were found to be the major compounds of the essential oil. Both the essential oil and the methanol extract of T. nummularius exhibited strong antioxidant activity in the four tested methods. Furthermore, the essential oil showed high inhibitory activity against acetyl-,butyryl-cholinesterase enzymes and very strong antimicrobial activity against all tested microorganisms. Besides, T. nummularius can be used both as rosmarinic acid source and as food supplement due to its non-aflatoxin content and high antioxidant, anticholinesterase and antimicrobial activities. (C) 2015 Elsevier B.V. All rights reserved