Effects Of Fosfomycin On The Intestinal Absorption And Pharmacokinetics Of Linezolid In Caco-2 Cell And In Rats

Objective:Linezolid combined with fosfomycin has been shown to have synergistic effects in vivo and in vitro,however,whether there exist drug-drug interaction is unclear.The main purpose of this study was to investigate the effects of various transporters and fosfomycin on the intestinal absorption of linezolid in Caco-2 cells,and the effects the effects of fosfomycin on pharmacokinetics of linezolid in rats.Method:?1?Caco-2 cell monolayer model was established and a sensitive LC-MS detection method was developed for quantation of linezolid to assess the transport characteristics of linezolid,the effect of P-gp inhibitor verapamil,MRP2 inhibitor probenecid,MCT inhibitor Phloretin and SGLT1 inhibitor Phlorizin on the intestinal absorption of linezolid and the effect of fosfomycin on the intestinal absorption of linezolid.?2?The effects of fosfomycin on the pharmacokinetics and tissue distribution of linezolid tissue in rats were studied after a single oral administration of linezolid and fosfomycin.Results:?1?Caco-2 cell monolayer model and the method of LC-MS detection of linezolid were established successfully.The intra-and inter-day precision?RSD?was within 9.39%and accuracy?RE?ranged from 85.49%-108.35%.?2?The transmembranetransportoflinezolidonCaco-2monolayerwas concentration-dependent,and the translocation per unit time increased with increasing concentration.In the study of the effect of inhibitor on linezolid,monocarboxyl was added.The monocarboxylate transparters inhibitor?phloretin?and the Na+-glucose co-transporter inhibitor?phloridin?resulted in significant differences in transport amount and Papp values of linezolid,while P-glycoprotein inhibitor?verapamil?and multidrug resistance-associated protein 2?probenecid?had no significant change in the transport amount and Papp value;the addition of fosfomycin had no significant effect on the transport amount and Papp value of linezolid;?3?Compared to single oral linezolid?50 mg/kg?,pharmacokinetic parameters(C_max,T_max,and AUC_last)in co-administration groups have no significant difference,and there was no significant difference in the tissues distribution of linezolid(C_max,AUC_last,and MRT_last).Conclution:Monocarboxylic acid transporters and Na+-glucose co-transporters are involved in the transmembrane transport of linezolid,substances that affect the activity of these transporters may interact with linezolid;Fosfomycin has no significant effect on the transport of linezolid;there was no drug-drug interactions between fosfomycin and linezolid after a single oral dose in rats,therefore,when both drugs were co-administered orally in a single dose,the dose of linezolid need not be adjusted.Since linezolid drug exposure in vivo and treatment time are closely related with adverse reactions,therapeutic drug monitoring?TDM?is still need during treatment.