Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents. Experimental Design: Uptake of [ 3 H]sorafenib or [ 3 H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters. Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9-and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls. Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporterrelated resistance mechanisms. (Clin Cancer Res 2009;15(19):6062-9) In recent years, eight orally administered, small-molecule tyrosine kinase inhibitors have been approved for the treatment of cancer in the United States. Among these, sorafenib and sunitinib are considered multikinase inhibitors because they inhibit multiple receptor and intracellular tyrosine kinases and exhibit antiangiogenic and antitumor activities (1-3). Sorafenib, an inhibitor of C-RAF, B-RAF, c-KIT, FLT-3, platelet-derived growth factor receptor β, and vascular endothelial growth factor receptors 1, 2, and 3, is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma (2). Sunitinib, an inhibitor of c-KIT, FLT-3, platelet-derived growth factor receptors α and β, and vascular endothelial growth factor 2, is approved for the treatment of advanced renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors (3). Sorafenib and sunitinib are being investigated for the treatment of other solid tumor malignancies (2, 3) and acute myelogenous leukemia (4,5).Studies have shown that tyrosine kinase inhibitors are substrates for and/or inhibit the function of various ATP-binding cassette (ABC) transporters, and these interactions may play an important role in modulating systemic pharmacokinetics of drugs, tissue and brain distribution, a...

A stable poly[2-acrylamido-2-methyl-1-propanesulfonic acid-co-poly(ethylene glycol) diacrylate] monolith was synthesized inside a 75-microm-i.d. capillary by photoinitiated copolymerization with water, methanol, and ethyl ether as porogens. The resulting monolith was evaluated for strong cation-exchange capillary liquid chromatography of both synthetic and natural peptides. Although the monolith possessed relatively strong hydrophobicity due to the use of 2-acrylamido-2-methyl-1-propanesulfonic acid as one monomer, the monolith had a high dynamic binding capacity of 157 microequiv of peptide/mL, or 332 mg of cytochrome c/mL. Exceptionally high resolution resulting from extremely narrow peaks was obtained, resulting in a peak capacity of 179 when using a shallow salt elution gradient. Although a second, naturally formed gradient might contribute to the sharp peaks obtained, high efficiency was mainly due to the use of poly(ethylene glycol) diacrylate as a biocompatible cross-linker.

Patients with sepsis commonly suffer from coagulation dysfunction and lead to the formation of thrombus. During the development of sepsis, neutrophils migrate from the circulating blood to infected tissues and mediate the formation of neutrophil extracellular traps (NETs) that kill pathogens. However, the overactivation of neutrophils can promote the formation of immunothrombosis and even cause disseminated intravascular coagulation (DIC), which damages microcirculation. The outcome of sepsis depends on early recognition and intervention, so clinical evaluation of NETs function may be a valuable biomarker for early diagnosis of sepsis. The interaction of NETs with platelets, complement, and endothelium mediates the formation of immunothrombosis in sepsis. Inhibiting the formation of NETs is also considered to be one of the potential treatments for sepsis. In this review, we will discuss the key role of neutrophils and NETs in sepsis and septic thrombosis, in order to reveal new mechanisms for thrombosis treatment of sepsis.