| With the increasing number of multidrug-resistant tuberculosis(MDR-TB)and extensively drug-resistant tuberculosis(XDR-TB)in recent years,tuberculosis(TB)still seriously threaten people’s health.In China,most of the MDR-TB and XDR-TB are separated from retreatment pulmonary tuberculosis which is complex and difficult to be treated.In order to increase therapeutic effect and prevent the emergence of drug-resistant tuberculosis,combination therapy is widely recommended in the treatment of TB.Especially for MDR-TB and XDR-TB,the regimens usually consist of five or more antituberculosis durgs.Drug-drug interaction(DDI)may influence pharmacokinetics and pharmacodynamics among different anti-tuberculosis drugs,so the therapeutic drug monitoring(TDM)is needed.This new chemical regimen for retreatment TB,which consist of moxifloxacin(Mfx),rifabutin(Rfb),ethambutol(EMB),pyrazinamide(PZA)and pasiniazid(Dip),has not been widely used in clinical,and its pharmacokinetic data is unclear,neither.With high performance liquid chromatography-ultraviolet(HPLC-UV)and high performance liquid chromatography-mass spectrometry(HPLC-MS),the blood samples were taken from mouse orbit and lung tissue were collected by microdialysis(MD),respectively.We conducted the pharmacokinetic study of this new chemical regimen for retreatment TB in plasma and lung tissue in rats,which can pave the way for its clinical use.1.The pharmacokinetic study of the new chemical regimen for retreatment TB in plasma of rats.In this part,HPLC-UV and HPLC-MS methods were used to evaluate the drug concentration in blood samples which were taken from orbit of SD rats after combined oral medication,and compared with the single oral medication,which can explore the pharmacokinetic characteristics and provide reference data and theoretical basis for the clinical use of this new regimen.The concentrations of Mfx,PZA and Dip were measured by HPLC-UV,While Rfb and EMB by HPLC-MS.18 rats were randomized into 6 groups: the Rfb group(30 mg/kg),Mfx group(40 mg/kg),PZA group(150 mg/kg),EMB group(90 mg/kg),Dip group(120mg/kg)and the combination group(the dosages of each medicine the same as single groups).Differences in pharmacokinetics of each medicines above were compared between the single and combination groups.A significant linearity was found in different concentrations of Rfb,Mfx,PZA,EMB and Dip respectively.The extraction recovery rates,inter-and intra-day precision of the five medicines all complied with the requirements of methodology.The pharmacokinetic parameters of the five medicines changed significantly in combination group compared with each single group(P<0.05).The area under time-concentration curve from zero to test time(AUC0-t)of Rfb in combination group reduced by 14.29 %,while the elimination half life(t1/2)extended from(14.62±1.90)h to(18.39±1.19)h,compared with single group(P<0.05).For Mfx and PZA,in combined group,the AUC0-t,t1/2 and peak concentration(Cmax)increased significantly,compared with single group(P < 0.05).In combination group,the AUC0-t of EMB declined from(12.32±1.61)mg·L-1·h-1 to(8.13±0.68)mg·L-1·h-1,and Cmax lowered by 65.46 %,compared with single group(P<0.05).The AUC0-t of paminosalicylic acid(PAS)in Dip declined by 42.93 %,and Cmax declined from(81.02±2.31)mg·L-1 to(44.09±4.74)mg/L,and the AUC0-t of isoniazide(INH)in Dip reduced by39.53 %,compared with single group(P<0.05).It is showed that although there are many differences in pharmacokinetics of Rfb,Mfx,PZA,EMB and Dip between combination and single medication in plasma of SD rats,the concentration of each drug in combination group was all higher than the minimum inhibitory concentration(MIC)of MTB.It indicated that the effect of Mfx and PZA improved,while the drug related adverse reactons should be monitored carefully.The absorption of Dip,Rfb and EMB is lower than single group,but the concentration in plasma is still higher than MIC of MTB.The dosage of each drug in this new regimen for retreatment tuberculosis should be adjusted for the curative effect and reducing the adverse reaction.2.The pharmacokinetic study of the new chemical regimen for retreatment TB in lung tissue of rats.In this part,HPLC-MS methods were used to evaluate the drug concentration in lung tissue samples which were collected by MD in SD rats after combined oral medication,and compared with the single oral medication,which can explore the pharmacokinetic characteristics and provide reference data and theoretical basis for the clinical use of this new regimen.The concentrations of Mfx,PZA,Dip,Rfb and EMB were evaluated by HPLC-MS.18 SD rats were randomized into 6 groups,including 5 single groups and a combination group.The drug dosage of Mfx,Rfb,EMB,PZA and Dip were 40 mg/kg,30 mg/kg,90mg/kg,150 mg/kg and 120 mg/kg respectively.The dosage of each drug in combination group is the same as in single groups.Differences in pharmacokinetics of each medicines above in the lung tissue were compared between the single and combination groups.A significant linearity was found in different concentrations of Rfb,Mfx,PZA,EMB and Dip respectively.The extraction recovery rates,inter-and intra-day precision of the five medicines all complied with the requirements of methodology.Compared with single group,pharmacokinetic parameters of the five medication in combination group changed significantly(P < 0.05).The area under time-concentration curve from zero to infinity(AUC0-∞)of Mfx in combination group increased by 79.62 %,compared with single group(P<0.05).Cmax of Rtb declined by 38.20%,compared with single group(P<0.05).For EMB,AUC0-t lowered by 30.13%,and Cmax declined from(1.64±0.26)mg/L to(1.12±0.06)mg/L,compared with single group(P < 0.05).For PZA,PAS and INH in Dip,in combined group,the AUC0-t and Cmax increased significantly,compared with single group(P<0.05).It is showed that the concentration of Mfx,PZA and Dip in lung tissue is increased in combination group,indicating that the anti-infective effect in lung TB may be improved.The absorption of Rfb and EMB is decreased in combination group than the single group,but the concentration in lung tissue is still higher than the MIC of TB.It means that this new regimen will play well in pulmonary TB with good pharmacokinetic basis. |
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