| Voriconazole?VRZ?is a highly fat-soluble triazole antifungal agent with broad-spectrum activity,which using the mode of nonlinear pharmacokinetics.The main metabolic enzyme of voriconazole is genetically polymorphic cytochrome P450?CYP?2C19 isoenzyme.which is the reason causing big individual difference and more adverse reactions.voriconazole adverse reactions included transient visual abnormalities,sepsis,and so on.The occurrence of adverse reactions is not only related to the drug itself,but also the preparation process and drug interactions contained in the preparation.The occurrence of adverse reactions is not only related to the drug itself,but also the preparation process and drug interactions contained in the preparation.This study is divided into two parts.In the first part,a set of stable,simple,accurate,and practical methods for the detection of voriconazole and its metabolite voriconazole N-oxide in vivo was established.Further detection was conducted on clinical samples.At the same time,these data were analyzed in the hope of guiding significance for clinical medication.In the second part,the pharmacokinetic characteristics of voriconazole in rats injection prepared by two different processes were compared.In the first part,we established methods for the determination of voriconazole and voriconazole N-oxide concentration in human plasma by high-performance liquid chromatography?HPLC?-ultraviolet?UV?detection.The procedure uses papaverine as the internal standard.Plasma samples were treated by acetonitrile protein precipitation.The mobile phase generally consists of 0.025 M sodium dihydrogen phosphate?containing triethylamine 400?L/L,p H=7.0 adjusted by 0.25 M sodium hydroxide?–acetonitrile?67:33?at the flow rate of 1 m L/min.The column temperature was 40?with dual-wavelength detection?255 nm,276 nm?.The results show that validated linear ranges of voriconazole and voriconazole N-oxide in plasma were 0.5?20.0?g/m L?r2=0.999 5?.The recoveries of the method are very good?within-sample recovery?.The method is simple and suitable for the clinical monitoring of voriconazole and the determination of its main metabolites.The blood valley concentration of voliconazole in 43 patients was further collected and measured.And the changes of total bilirubin,alanine aminotransferase,?-glutamyltransferase l-glutaminotransferase,and creatinine were also analyzed.The results showed that the above clinical indicators were abnormal when the valley concentration of voriconazole was high,but there was no significant difference in the concentration of voriconazole N-oxide?In the second part,we established a high-performance liquid chromatoid-tandem mass spectrometry?HPLC-MS/MS?method for determination of voriconazole and its metabolites,voriconazole N-oxide,in rat plasma.We investigated the pharmacokinetics and tissue distribution of voriconazole and its metabolites in rats from two commonly used voriconazole injections with different excipients in two different doses.The high dose was equivalent to the human load dose,and the low dose was equivalent to the human maintenance dose.In the high-dose experiment,male wistar rats were divided into two groups by the method of random number table.Voriconazole injection of two different preparation processes was administered by single-dose tail vein injection.The rats in the low-dose experiment were designed in a stratified zone,with gender as the stratification factor.Then,blood samples or organs were taken at different time points,and the concentrations of voriconazole and voriconazole N-oxide were determined by the method of HPLC-MS/MS.Finally,the tissue distribution of the two injections and the metabolite voriconazole N-oxide were compared.The results showed that the pharmacokinetic of the two voriconazole injections and the metabolite voriconazole N-oxide in rats were not statistically significant.The results of this study indicate that the methods we established in the first part for the determination of voriconazole and voriconazole N-oxide concentrations in human plasma is suitable for the monitoring of voriconazole clinical samples.The results showed that the increased concentration of voriconazole was correlated with the abnormal indexes of total bilirubin,alanine aminotransferase,?-glutamyl transferase,and creatinine.The method of HPLC-MS/MS established in the second part were suitable for the determination of voriconazole and its nitrogen oxide concentration in rats.Meanwhile,the results about detection of single cycle and single dose?25 mg/kg?in Wistar male rats,there was no significant difference in the pharmacokinetics of two voriconazole injections and the metabolite voriconazole N-oxide in rats.We investigated the concentration of Volconazole in heart,liver,spleen,lung,kidney and brain tissues at 5min,6h and 12h after administration,and found that the concentration of domestic Voriconazole is higher than that of imported voriconazole and the AUC0?24h of domestic voriconazole is higher than that of imported voriconazole.There was no statistically significant difference in pharmacokinetics of voriconazole injection and its metabolite nitrogen oxide in rats with single cycle and single dose?40 mg/kg?.In addition,the AUC0?24h of domestic voriconazole is higher than that of imported voriconazole in six kinds of tissues including heart,liver,spleen,lung,kidney and brain. |
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