Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin in vivo with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify cinobufotalin in rat plasma. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of cinobufotalin in normal and DEN-injured rats after intravenous (i.v.) injection at a dosage of 2.5 mg/kg. Cinobufotalin pharmacokinetics was well described by the two-compartment pharmacokinetic model and the PK parameters were calculated using WinNonlin 3.3 software. The transfer rate constant of cinobufotalin from the central compartment to the peripheral compartment (k12) in DEN-injured rats was significantly greater than that in normal rats (p < 0.01), accompanied by the shorter half-life for the distribution phase (t1/2α). Additionally, the elimination rate constant (K10) and clearance (CL) values in DEN-injured rats were significantly higher than that in normal rats (p < 0.05 for K10 and p < 0.001 for CL, respectively). Therefore, the values of areas under concentration – time curve (AUC) and the liver concentration of cinobufotalin in DEN-injured rats was obviously lower than that in normal rats (p < 0.001 and p < 0.01, respectively). This indicated that the PK behaviors of cinobufotalin will be altered in rats with HCC. In addition, P-glycoprotein (P-gp) has shown higher expression in live tissues of DEN-injured rats. Furthermore, cinobufotalin was identified as the substrate of P-gp using MDCK II and MDCK-MDR1 cell models for the first time. Consequently, P-gp will play an important role in the disposition of cinobufotalin in vivo, which provided a new combination therapy for the clinical treatment of HCC

The complete chloroplast genome of Phaeodactylum tricornutum ICE-H isolated from the Antarctic sea ice

Phaeodactylum tricornutum ICE-H is a single-cell eukaryotic alga that can grow in the extreme Antarctic environment. The complete chloroplast genome of Phaeodactylum tricornutum ICE-H was assembled with the Illumina sequencing. The chloroplast genome was 117,363 bp in size, containing a large single-copy region (LSC, 63,668 bp), a small single-copy region (SSC, 39,871 bp), and a pair of inverted repeat regions (IRs, 13,824 bp each). The overall GC content was 32.15%. A total of 168 genes were predicted including 132 protein-coding genes, 30 tRNAs, and 6 rRNAs. Phylogenetic analysis indicated that Phaeodactylum tricornutum ICE-H was closely related to Didymosphenia geminata