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1. TM-2 is a promising novel semi-synthetic taxane derivative with greater antitumor activity especially against resistant tumors and lower toxicity compared with docetaxel. Information on distribution and excretion of the pharmaceutical in animals, as well as biochemical information relevant to potential drug interactions should normally be evaluated prior to human clinical trials. 2. The present study investigated the tissue distribution and excretion of TM-2 in animals following intravenous administration for further advancement of the molecule. The potential inductive effect of TM-2 on cytochrome P450 iso-enzymes CYP 3A1 in rats was also evaluated. 3. The tissue distribution study in mice showed that TM-2 was rapidly dispersed in the various tissues and peak concentration levels were achieved within 0.083–1 h. The highest concentration was detected in pancreas, followed by lung, kidney, spleen, heart and liver. TM-2 was mainly excreted in the feces via the bile (0.14% of the dose) and urinary excretion was minimal (0.007%). TM-2 increased CYP3A1 enzyme activities with time and dose dependence in rat liver microsome. 4. This important data serve as a useful resource to support further research of TM-2 and allow intelligent assessment of toxicology andin vivoactivity testing performed in animals. [ABSTRACT FROM PUBLISHER]

Biological barrier plays a crucial role for organisms against the possible toxicity from engineered nanomaterials (ENMs). Graphene oxide (GO) has been proven to cause potential toxicity on organisms. However, the molecular mechanisms for intestinal barrier of animals against GO toxicity are largely unclear. Usingin vivoassay system ofCaenorhabditis elegans, we found that mutation of genes encoding core p38 mitogen-activated protein kinase (MAPK) signaling pathway caused susceptible property to GO toxicity and enhanced translocation of GO into the body of nematodes. Genetic assays indicated that SKN-1/Nrf functioned downstream of p38 MAPK signaling pathway to regulate GO toxicity and translocation. Transcription factor of SKN-1 could regulate GO toxicity and translocation at least through function of its targeted gene ofgst-4encoding one of phase II detoxification proteins. Moreover, intestine-specific RNA interference (RNAi) assay demonstrated that the p38 MAPK-SKN-1/Nrf signaling cascade could function in intestine to regulate GO toxicity and intestinal permeability in GO exposed nematodes. Therefore, p38 MAPK-SKN-1/Nrf signaling cascade may act as an important molecular basis for intestinal barrier against GO toxicity in organisms. Exposure to GO induced significantly increased expression of genes encoding p38 MAPK-SKN-1/Nrf signaling cascade, which further implies that the identified p38 MAPK-SKN-1/Nrf signaling cascade may encode a protection mechanism for nematodes in intestine to be against GO toxicity. [ABSTRACT FROM AUTHOR]