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 co...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.展开更多
Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imi...Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imipenem/cilastatin is a rare condition.Patient’s Concern:A 45-year-old male patient,who previously suffered from a urinary tract infection and treated with imipenem/cilastatin antibiotic,was presented to us with acute respiratory distress,soon after the initiation of the antibiotic.Computed tomography identified pulmonary infiltrates in the upper and middle lung fields and eosinophils were found to account for 36%of differential count of the broncho-alveolar lavage fluid.He also developed peripheral eosinophilia as the disease progressed.Diagnosis:AEP,secondary to imipenem/cilastatin therapy.Interventions:Steroid therapy was administered and imipenem/cilastatin antibiotic was discontinued.Outcomes:The patient improved completely following the therapy and had clear lung fields on follow-up.Lessons:Imipenem/cilastatin is an uncommon cause of AEP and requires close monitoring during therapy.展开更多
Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infection...Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections Methods A total of 182 hospitalized patients were enrolled in the study 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion The duration of treatment was 7-14 days for both groups Results Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups 93 (76%) of 123 strains isolated from patients produced β lactamases Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group The adverse drug reaction rates were 9 7% and 8 6%, respectively The results showed that there were no statistical differences between these two groups ( P >0 05) Conclusion Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta lactamase producing strains展开更多
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 stud...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.展开更多
基金supported by a grant from the National Natural Science Foundation of China (No. 81874324,81473280,U1608283)the Natural Science Foundation of Liaoning (No. 20170540293)Dalian Science and technology innovation fund (No. 2018J12SN065).
文摘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.
文摘Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imipenem/cilastatin is a rare condition.Patient’s Concern:A 45-year-old male patient,who previously suffered from a urinary tract infection and treated with imipenem/cilastatin antibiotic,was presented to us with acute respiratory distress,soon after the initiation of the antibiotic.Computed tomography identified pulmonary infiltrates in the upper and middle lung fields and eosinophils were found to account for 36%of differential count of the broncho-alveolar lavage fluid.He also developed peripheral eosinophilia as the disease progressed.Diagnosis:AEP,secondary to imipenem/cilastatin therapy.Interventions:Steroid therapy was administered and imipenem/cilastatin antibiotic was discontinued.Outcomes:The patient improved completely following the therapy and had clear lung fields on follow-up.Lessons:Imipenem/cilastatin is an uncommon cause of AEP and requires close monitoring during therapy.
文摘Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections Methods A total of 182 hospitalized patients were enrolled in the study 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion The duration of treatment was 7-14 days for both groups Results Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups 93 (76%) of 123 strains isolated from patients produced β lactamases Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group The adverse drug reaction rates were 9 7% and 8 6%, respectively The results showed that there were no statistical differences between these two groups ( P >0 05) Conclusion Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta lactamase producing strains
基金supported by a grant from the National Natural Science Foundation of China,China(Nos.81874324,81473280,and U1608283)Dalian Science and technology innovation found,China(No.2018J12SN065)
文摘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.
