Pharmacokinetic Drug Interaction between Tofacitinib and Voriconazole in Rats.

Fungal infections are prevalent in patients with immune diseases. Voriconazole, a triazole antifungal drug, inhibits the cytochromes CYP3A4 and CYP2C, and tofacitinib, a Janus kinase inhibitor for the treatment of rheumatoid arthritis, is metabolized by CYP3A4 and CYP2C19 in humans. Here, we investigated their interaction during simultaneous administration of both drugs to rats, either intravenously or orally. The area under the plasma concentration-time curve from time zero to time infinity (AUC) of tofacitinib was significantly greater, by 166% and 171%, respectively, and the time-averaged non-renal clearance (CLNR) of tofacitinib was significantly slower (59.5%) than that for tofacitinib alone. An in vitro metabolism study showed non-competitive inhibition of tofacitinib metabolism in the liver and intestine by voriconazole. The concentration/apparent inhibition constant (Ki) ratios of voriconazole were greater than two, indicating that the inhibition of tofacitinib metabolism could be due to the inhibition of the CYP3A1/2 and CYP2C11 enzymes by voriconazole. The pharmacokinetics of voriconazole were not affected by the co-administration of tofacitinib. In conclusion, the significantly greater AUC and slower CLNR of tofacitinib after intravenous and oral administration of both drugs were attributable to the non-competitive inhibition of tofacitinib metabolism via CYP3A1/2 and CYP2C11 by voriconazole in rats.

A Complicated Relationship: Glycosylation, Ca(II), and Primary Sequence Affect the Interactions and Kinetics between Two Model Mollusk Shell Intracrystalline Nacre Proteins.

The formation of the mollusk shell requires the participation of proteins, many of which may be interactive with one another. We examined a model protein pair system from the mollusk Haliotis rufescens, wherein we probed the interactions between recombinant forms of two major nacre layer proteins, AP7, and the glycoprotein, AP24. Here, the focus was on the impact that the AP24 glycosylation and primary sequence had on AP24-AP7 binding. We find that both the glycosylated and nonglycosylated variants of AP24 bound to AP7 but with different quantities, kinetics, and internal rearrangements. Moreover, the binding of AP7 with nonglycosylated and glycosylated AP24 was found to be Ca(II)-dependent and -independent, respectively. Yet both variants of AP24 combine with AP7 to form hybrid hydrogel particles that are similar in their physical properties. Thus, AP7 and AP24 protein sequences are interactive and form hydrogels, but the interactions are tuned by glycosylation and Ca(II). These features may have an impact on the nacre matrix formation.

Sea Urchin Spicule Matrix Proteins Form Mesoscale "Smart" Hydrogels That Exhibit Selective Ion Interactions.

In the sea urchin embryo spicule, there exists a proteome of >200 proteins that are responsible for controlling the mineralization of the spicule and the formation of a fracture-resistant composite. In this report, using recombinant proteins, we identify that two protein components of the spicule, SM30B/C and SM50, are hydrogelators. Because of the presence of intrinsic disorder and aggregation-prone regions, these proteins assemble to form porous mesoscale hydrogel particles in solution. These hydrogel particles change their size, organization, and internal structure in response to pH and ions, particularly Ca(II), which indicates that these behave as ion-responsive or "smart" hydrogels. Using diffusion-ordered spectroscopy NMR, we find that both hydrogels affect the diffusion of water, but only SM50 affects the diffusion of an anionic solute. Thus, the extracellular matrix of the spicule consists of several hydrogelator proteins which are responsive to solution conditions and can control the diffusion of water and solutes, and these proteins will serve as a model system for designing ion-responsive, composite, and smart hydrogels.