Organic anion transporters also mediate the drug–drug interaction between imipenem and cilastatin

This study aimed to clarify that organic anion transporters(OATs)mediate the drug–drug interaction(DDI)between imipenem and cilastatin.After co-administration with imipenem,the plasma concentrations and the plasma concentration-time curve(AUC)of cilastatin were significantly increased,while renal clearance and cumulative urinary excretion of cilastatin were decreased.At the same time,imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1(hOAT1)-HEK293 and human OAT3(hOAT3)-HEK293 cells.Probenecid,p-aminohippurate,and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1-and hOAT3-HEK 293 cells,respectively.The uptakes of imipenem and cilastatin in hOAT1-and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 cells.Moreover,the K m values of cilastatin were increased in the presence of imipenem with unchanged V max,indicating that imipenem inhibited the uptake of cilastatin in a competitive manner.When imipenem and cilastatin were co-administered,the level of imipenem was higher compared with imipenem alone both in vivo and in vitro.But,cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1(DPEP1)was silenced by RNAi technology in hOAT1-and hOAT3-HEK 293 cells.In conclusion,imipenem and cilastatin are the substrates of OAT1 and OAT3.OAT1 and OAT3 mediate the DDI between imipenem and cilastatin.Meanwhile,cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement.

Piperacillin enhances the inhibitory effect of tazobactam on β-lactamase through inhibition of organic anion transporter 1/3 in rats

To assess the mechanism of the pharmacokinetic interaction between piperacillin and tazobactam,renal excretion and pharmacokinetic studies of piperacillin/tazobactam were investigated in normal and bacteremia rats.A bacteremia model was established to investigate the pharmacokinetic properties of piperacillin and tazobactam under different conditions.Renal slices were taken to examine the uptake of piperacillin and tazobactam.Pharmacokinetic studies ofβ-lactamase in rats were performed to study the contribution of rOat1/3 to the inhibition of tazobactam onβ-lactamase.The AUC(from 2.93±0.58 to 6.52±1.44 mg·min/ml)and the plasma clearance(CL P)(from 2.41±1.20 to 0.961±0.212 ml/min/kg)of tazobactam were both altered after the intravenous coadministration of piperacillin and tazobactam in the bacteremia rats.The renal clearance(CL R)of tazobactam decreased from 1.30±0.50 to 0.361±0.043 ml/min/kg.In summary,there was a beneficial interaction between piperacillin and tazobactam mediated by rOat1 and rOat3.Piperacillin enhances the inhibitory effect of tazobactam onβ-lactamase through the inhibition of rOat1 and rOat3 in rats.The contribution rate of rOat1/3 for the synergistic effect was 20%when the two drugs were coadministered.

Cilastatin protects against imipenem-induced nephrotoxicity via inhibition of renal organic anion transporters(OATs)

Imipenem is a carbapenem antibiotic. However, Imipenem could not be marketed owing to its instability and nephrotoxicity until cilastatin, an inhibitor of renal dehydropeptidase-I(DHP-I),was developed. In present study, the potential roles of renal organic anion transporters(OATs) in alleviating the nephrotoxicity of imipenem by cilastatin were investigated in vitro and in rabbits. Our results indicated that imipenem and cilastatin were substrates of h OAT1 and h OAT3. Cilastatin inhibited h OAT1/3-mediated transport of imipenem with IC50 values comparable to the clinical concentration, suggesting the potential to cause a clinical drug–drug interaction(DDI). Moreover,imipenem exhibited h OAT1/3-dependent cytotoxicity, which was alleviated by cilastatin and probenecid. Furthermore, cilastatin and probenecid ameliorated imipenem-induced rabbit acute kidney injury, and reduced the renal secretion of imipenem. Cilastatin and probenecid inhibited intracellular accumulation of imipenem and sequentially decreased the nephrocyte toxicity in rabbit primary proximal tubule cells. Renal OATs, besides DHP-I, was also the target of interaction between imipenem and cilastatin, and contributed to the nephrotoxicity of imipenem. This therefore gives in part the explanation about the mechanism by which cilastatin protected against imipenem-induced nephrotoxicity. Thus, OATs can potentially be used as a therapeutic target to avoid the renal adverse reaction of imipenem in clinic.

Topological-based bottleneck analysis and improvement strategies for traffic networks

A method is proposed to find key components of traffic networks with homogenous and heterogeneous topologies, in which heavier traffic flow is transported. One component, called the skeleton, is the minimum spanning tree (MST) based on the zero flow cost (ZCMST). The other component is the infinite incipient percolation cluster (IIC) which represents the spine of the traffic network. Then, a new method to analysis the property of the bottleneck in a large scale traffic network is given from a macroscopic and statistical viewpoint. Moreover, three effective strategies are proposed to alleviate traffic congestion. The significance of the findings is that one can significantly improve the global transport by enhancing the capacity in the ZCMST with a few links, while for improving the local traffic property, improving a tiny fraction of the traffic network in the IIC is effective. The result can be used to help traffic managers prevent and alleviate traffic congestion in time, guard against the formation of congestion bottleneck, and make appropriate policies for traffic demand management. Meanwhile, the method has very important theoretical significance and practical worthiness in optimizing traffic organization, traffic control, and disposal of emergency.

Risk warning technologies and emergency response mechanisms in Sichuan-Tibet Railway construction

Safety is one of the most critical themes in any large-scale railway construction project.Recognizing the importance of safety in railway engineering,practitioners and researchers have proposed various standards and procedures to ensure safety in construction activities.In this study,we first review four critical research areas of risk warning technologies and emergency response mechanisms in railway construction,namely,(i)risk identification methods of large-scale railway construction projects,(ii)risk management of large-scale railway construction,(iii)emergency response planning and management,and(iv)emergency response and rescue mechanisms.After reviewing the existing studies,we present four corresponding research areas and recommendations on the Sichuan-Tibet Railway construction.This study aims to inject new significant theoretical elements into the decision-making process and construction of this railway project in China.

Coupling analysis of passenger and train flows for a large-scale urban rail transit system

Coupling analysis of passenger and train flows is an important approach in evaluating and optimizing the operation efficiency of large-scale urban rail transit(URT)systems.This study proposes a passenger–train interaction simulation approach to determine the coupling relationship between passenger and train flows.On the bases of time-varying origin–destination demand,train timetable,and network topology,the proposed approach can restore passenger behaviors in URT systems.Upstream priority,queuing process with first-in-first-serve principle,and capacity constraints are considered in the proposed simulation mechanism.This approach can also obtain each passenger’s complete travel chain,which can be used to analyze(including but not limited to)various indicators discussed in this research to effectively support train schedule optimization and capacity evaluation for urban rail managers.Lastly,the proposed model and its potential application are demonstrated via numerical experiments using real-world data from the Beijing URT system(i.e.,rail network with the world’s highest passenger ridership).

Collaborative matching of ridesplitting and connection in the ridesourcing market

The emergence of ridesplitting as a form of ridesourcing reduces the use of vehicles on the road.When connecting multiple ridesplitting orders and single orders to the sharing path,it can achieve higher sharing efficiency.This paper aims to further improve the vehicle sharing rate,and explore the impact of multi-mode sharing using the order data of Haikou,China provided by DiDi Chuxing.A shareability network combining the ridesplitting network and connection network is built based on the order data.We propose the on-demand matching algorithm with four matching objectives to obtain the dispatching strategy.The results show that the percentage of shared trips can reach 99%,the vehicle saving rate can reach 83%,and the average number of shared trips served by shared vehicles can reach about 6 with the time interval 20 min and maximum delay 300 s.When the maximum delay is 300 s,the percentage of orders that can be shared by multiple modes is about 30%.The average delay,idling time and waiting time of shared orders are slightly higher than the corresponding maximum delay,and increase with the increase of the maximum delay,while the change of saving time is the opposite.The proposed algorithm considers the impact of the maximum delay,which,compared with the maximum matching algorithm,has a significant improvement.