三种抗生素在唾液、龈沟液中的分布及其与血药浓度相关性研究
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摘要
目前口腔感染治疗采用的抗菌素既有广谱抗菌素,也有对厌氧性革兰氏阳性和阴性杆菌和球菌均有较强的抗菌作用的咪唑类衍生物。随着抗生素的滥用,药物的不良反应与耐药性正日渐引起重视。治疗药物监测(therapeuticdrug monitoring,TDM)通过现代分析技术,测定血液或其他体液中的药物浓度,可以协助医生选择和调整用药方案,减少不良反应和耐药性的发生。目前研究表明,某些药物在唾液中的药物浓度与血药浓度有一种持续可预测的关联,可以用于治疗药物监测。与血液相比,唾液取样方便、无创,患者易于接受。用唾液替代血液用于治疗药物的监测已成为目前的研究热点。头孢哌酮(cefoperazone,CPZ)、甲磺酸帕珠沙星(pazufloxacin,PAZ)、奥硝唑(ornidazole,ONZ)是目前口颌面抗感染治疗常用的三种新型抗生素。关于这三种药物在唾液和龈沟液中的分布目前尚未见报道,能否利用唾液进行这三种药物浓度的监测尚不清楚。另外,由于龈沟液与唾液来源与成分不同,以往对龈沟液进行治疗药物监测的研究也较少,能否利用龈沟液进行这三种药物浓度监测同样也有待研究。就此,本研究观察了头孢哌酮、甲磺酸帕珠沙星和奥硝唑在唾液和龈沟液中的分布,探讨利用唾液、龈沟液进行这三种药物浓度监测的可行性,研究分为两个部分。
一、三种药物高效液相色谱法的建立
目的:建立唾液、龈沟液、血液中奥硝唑、甲磺酸帕珠沙星、头孢哌酮的RP-HPLC分析方法。方法:头孢哌酮和奥硝唑的色谱柱均为Agilent ZorbaxSB-C_(18)(5μm,150mm×4.6mm);甲磺酸帕珠沙星的色谱柱为Agilent ZorbaxSB-C_(18)(5μm,250mm×4.6mm);头孢哌酮流动相为乙腈-0.02mol/L磷酸二氢钾(1:6)。甲磺酸帕珠沙星流动相为乙腈-磷酸三乙胺溶液(0.5%磷酸,1%三乙胺)=(155:850)。奥硝唑的流动相为甲醇-水(25:75)。紫外检测波长分别为254、245、316nm。流速均为1.0ml/min,柱温为室温;进样量20μl。三种样本处理中,头孢哌酮先用乙腈沉淀蛋白、再通过二氯甲烷萃取;甲磺酸帕珠沙星采用甲醇沉淀去杂质;奥硝唑用5%的异丙醇氯仿萃取。结果:本实验条件下,唾液、龈沟液和血液中的三种药物均能完全分离,峰形良好。药物浓度均呈现良好线性回归(r＞0.999)。日内、日间变异系数均＜5%,绝对回收率＞80%。结论:本试验建立的HPLC方法对头孢哌酮、甲磺酸帕珠沙星、奥硝唑这三种抗生素检测灵敏度高、方法稳定、可靠,可用于唾液、龈沟液和血液样本中这三种药物的检测。
二、三种抗生素在唾液、龈沟液中的分布研究
目的:观察头孢哌酮、甲磺酸帕珠沙星、奥硝唑在唾液和龈沟液中的分布,分析与血药浓度的相关性,探讨采用唾液、龈沟液监测这三种药物的浓度的可行性。方法:20名健康志愿者分为三组分别给药,头孢哌酮1.5g/人次,甲磺酸帕珠沙星0.3g/人次,奥硝唑0.5g/人次,单次静滴30min。应用RP-HPLC法测定唾液、龈沟液中的药物浓度,进行药代动力学拟合计算,分析唾液或龈沟液的药代动力学及与血药浓度的相关性。结果:1.奥硝唑在唾液中药物浓度与血药浓度呈显著相关,相关系数为0.825～0.969。奥硝唑在唾液和血液中的浓度比值(S/P)为0.99±0.13。唾液中头孢哌酮和甲磺酸帕珠沙星浓度与血药浓度无显著相关性,三种药物在龈沟液中浓度与血药浓度均无显著相关性。2.头孢哌酮峰浓度依次为唾液(0.41±0.51μg/mL)＜龈沟液(38.98±29.23μg/mL)＜血液(110.40±32.66μg/mL)。甲磺酸帕珠沙星峰浓度依次为唾液(0.40±0.13μg/mL)＜龈沟液(1.68±1.03μg/mL)＜血清(9.46±3.38μg/mL)。头孢哌酮和甲磺酸帕珠沙星在三种体液中的峰浓度均有显著差异(p＜0.05)。奥硝唑峰浓度依次为龈沟液(5.61±1.24μg/mL)＜血液(6.45±1.21μg/mL)＜唾液(6.89±1.50μg/mL),三者间无显著性差异(p＞0.05)。3.奥硝唑在唾液中的分布符合三室模型,Cmax为7.05±1.36μg/mL,t1/2β为15.13±2.63h,AUC0-∞为80.58±17.2μg.h/ml,AUC0-t为68.26±13.79μg.h/ml;甲磺酸帕珠沙星在部分受试者唾液中的分布符合二室模型,Cmax为0.46±0.13μg/mL,t1/2β为1.21±1.03h,AUC0-∞为0.53±0.13μg.h/ml,AUC0-t为0.46±0.17μg.h/ml;头孢哌酮在唾液中的分布个体差异明显,无法得到良好的房室拟合模型。4.三种药物在龈沟液中的分布由于个体差异较大,无法得到良好的药代动力学模型拟合结果。结论:1.奥硝唑可以采用唾液药物浓度进行治疗药物监测。头孢哌酮、甲磺酸帕珠沙星不能采用唾液进行药物监测。2.龈沟液不能替代血液进行这三种抗生素的治疗药物监测。3.奥硝唑在唾液中的分布迅速、持久,在唾液、龈沟液中浓度均较高。头孢哌酮和甲磺酸帕珠沙星在唾液、龈沟液中浓度较低。
Orofacial infection is usually mixed infection of aerobic and anaerobic bacteria, the current antibiotics against those pathogenic bacterium include both wide-spectrum antibiotics and those which have strong antibacterial action specific against gram-positive and gram-negative bacillus or coccus. With the growing abuse of antibiotics, the drug adverse reaction and drug resistance are receiving more and more attention. Therapeutic drug monitoring is to messure the drug concentration in blood or other body fluid by morden analytical technology, providing the renferences for doctors to select and adjust drug regim, to prevent and decrease the drug adverse reaction and drug resistance. At present, some research have proved that persistent and predictable correlation exist between the saliva concentration and serum concentration for certain drugs, for these drugs, the saliva can replace serum to monitor the serum concentration, this method is simple, non-invasive, and easy for patient to accept. More and more researches have now focused on this area. Cefoperazone (CPZ), pazufloxacin (PAZ), ornidazole (ONZ) are three new antibiotics used against orofacial infection, their distribution in saliva and gingival crevicular fluid (GCF) remain unclear, furtherly it is still unknown whether saliva can be used to mornitor the drug concentration for these three antibiotics. Besides, the past research about the distribution of these drugs in GCF and drug serum concentration monitoring with GCF are scared, based on those status, this research aimed to investigate the distribution of CPZ, PAZ and ONZ in saliva, GCF and serum to determine the feasibility of monitoring drug serum concentration with saliva and GCF, the whole research have two parts:
The construction HPLC method for three antibiotics
Objective: To set up high-performance liquid chromatography (HPLC) method for detecting CPZ, PAZ and ONZ in saliva, GCF and serum. Method: Chromatography was carried out on a reversed-phase column (Agilent Zorbax SB-C_(18) ;5μm, 150mmx4.6mm) for CPZ and ONZ, Agilent Zorbax SB-C_(18) (5μm, 250mmx4.6mm) for PAZ. The mobile phase for CPZ consisted of acetonitrile and 0.02mol/L KH_2PO_4(1:6); the mobile phase for PAZ was a mixture of acetonitrile and 0.5% phosphoric acid containing 1% triethylamine (155:850); the mobile phase for ONZ was methanol-water (25:75). 20μl of the resulting solution was injected into the HPLC system at a flow rate of 1.0ml/ min, and the wavelength was seted at 254, 245 and 316 nm, respectively. The samples were deproteinised with acetonitrile, then extracted with methylene dichloride for CPZ; for PAZ, methanol was used to precipitate the impurity in the samples; samples were extracted with isopropanol-chloroform (5: 95) for ONZ. Results: The CPZ, PAZ and ORN in saliva and serum were separated on the baseline, the calibration curves showd favorable linear regression (r>0.999). The coefficients of variation for within-day and between-day performance were found to be all less than 5%; the recovery rates were all above 80%. Conclusion: The HPLC methods for messureing the concentration of cefoperazone, pazufloxacin and ornidazole had a high sensitivity, the precision and recovery rates were high and stable. These methods could be applied for the detections of these drugs in saliva, GCF and serum.
The distribution of three antibiotics in saliva and GCF
Objective: To observe the distribution of three antibiotics in saliva and GCF, and to determine the feasibility of monitoring serum drug concentration with saliva and GCF. Method: Twenty healthy volunteers were divided into three groups: 1) cefoperazone 1.5g; 2) pazufloxacin 0.3g; 3) ornidazole 0.6g, all the subjects were intervenously administrated antibiotics in 30 min. The concentrations of CPZ, PAZ and ONZ in saliva, GCF, and serum were assayed by HPLC, analysis of the correlation of the drug concentration in saliva or gingival crevicular fluid to that in serum was then performed. Results: 1. The concentration of ORN in saliva was strongly associated with plasma concentration (r=0.825～0.969), the ratio of saliva-to-plasma concentration (S/P) of ONZ was 0.99±0.13. The concentration of all the three antibiotics in GCF had no significant association with plasma concentration, both the concentration of CPZ and PAZ in saliva and GCF had no significant association with plasma concentration. 2. The distribution of all the three antibiotics in GCF could not achieve suitable compartment model because of obvious individual differences. 3. The Cmax of CPZ in samples decreased in order of serum (110.40±32.66μg/mL), GCF (38.98±29.23μg/mL), saliva (0.41±0.51μg/mL), for PAZ that is serum (9.46±3.38μg/mL), GCF (1.68±1.03μg/mL), saliva (0.40±0.13μg/mL), the Cmax of CPZ and PAZ in three samples were all significantly different (p<0.05); the highest Cmax of ONZ was in saliva (6.89±1.50μg/mL), next is serum (6.45±1.21μg/mL), the lowest was in GCF (5.61±1.24μg/mL). The distribution of ORN in saliva corresponded to three compartment model. The pharmacokinetic parameters were as follows: Cmax(7.05±1.36)μg/mL, t1/2β(15.13±2.63) h,AUC0-∞(80.58±17.2)μg.h/ml, AUCO-t (68.26±13.79)μg.h/ml; the distribution of PAZ in saliva of partial subjects corresponded to three compartment model, the pharmacokinetic parameters were as follows: Cmax(0.46±0.13μg/mL), t1/2β(1.21±1.03h), AUC0-∞(0.53±0.13μg.h/ml), AUC0-t(0.46±0.17μg.h/ml). For great individual differences of CPZ in saliva and GCF, no favorable compartment model could be achieved. Conclusion: 1. While ORN determined in saliva seems to be suitable for therapeutic drug monitoring, it could not be applied for CPZ and PAZ. 2. All the three antibiotics determined in GCF seems to be unsuitable for therapeutic drug monitoring. 3.ORN could rapidly distribute to saliva, and had highest concentration in saliva and relative longer elimination time, and the concentration of CPZ and PAZ in saliva and GCF were low.
一、三种药物高效液相色谱法的建立
目的:建立唾液、龈沟液、血液中奥硝唑、甲磺酸帕珠沙星、头孢哌酮的RP-HPLC分析方法。方法:头孢哌酮和奥硝唑的色谱柱均为Agilent ZorbaxSB-C_(18)(5μm,150mm×4.6mm);甲磺酸帕珠沙星的色谱柱为Agilent ZorbaxSB-C_(18)(5μm,250mm×4.6mm);头孢哌酮流动相为乙腈-0.02mol/L磷酸二氢钾(1:6)。甲磺酸帕珠沙星流动相为乙腈-磷酸三乙胺溶液(0.5%磷酸,1%三乙胺)=(155:850)。奥硝唑的流动相为甲醇-水(25:75)。紫外检测波长分别为254、245、316nm。流速均为1.0ml/min,柱温为室温;进样量20μl。三种样本处理中,头孢哌酮先用乙腈沉淀蛋白、再通过二氯甲烷萃取;甲磺酸帕珠沙星采用甲醇沉淀去杂质;奥硝唑用5%的异丙醇氯仿萃取。结果:本实验条件下,唾液、龈沟液和血液中的三种药物均能完全分离,峰形良好。药物浓度均呈现良好线性回归(r＞0.999)。日内、日间变异系数均＜5%,绝对回收率＞80%。结论:本试验建立的HPLC方法对头孢哌酮、甲磺酸帕珠沙星、奥硝唑这三种抗生素检测灵敏度高、方法稳定、可靠,可用于唾液、龈沟液和血液样本中这三种药物的检测。
二、三种抗生素在唾液、龈沟液中的分布研究
目的:观察头孢哌酮、甲磺酸帕珠沙星、奥硝唑在唾液和龈沟液中的分布,分析与血药浓度的相关性,探讨采用唾液、龈沟液监测这三种药物的浓度的可行性。方法:20名健康志愿者分为三组分别给药,头孢哌酮1.5g/人次,甲磺酸帕珠沙星0.3g/人次,奥硝唑0.5g/人次,单次静滴30min。应用RP-HPLC法测定唾液、龈沟液中的药物浓度,进行药代动力学拟合计算,分析唾液或龈沟液的药代动力学及与血药浓度的相关性。结果:1.奥硝唑在唾液中药物浓度与血药浓度呈显著相关,相关系数为0.825～0.969。奥硝唑在唾液和血液中的浓度比值(S/P)为0.99±0.13。唾液中头孢哌酮和甲磺酸帕珠沙星浓度与血药浓度无显著相关性,三种药物在龈沟液中浓度与血药浓度均无显著相关性。2.头孢哌酮峰浓度依次为唾液(0.41±0.51μg/mL)＜龈沟液(38.98±29.23μg/mL)＜血液(110.40±32.66μg/mL)。甲磺酸帕珠沙星峰浓度依次为唾液(0.40±0.13μg/mL)＜龈沟液(1.68±1.03μg/mL)＜血清(9.46±3.38μg/mL)。头孢哌酮和甲磺酸帕珠沙星在三种体液中的峰浓度均有显著差异(p＜0.05)。奥硝唑峰浓度依次为龈沟液(5.61±1.24μg/mL)＜血液(6.45±1.21μg/mL)＜唾液(6.89±1.50μg/mL),三者间无显著性差异(p＞0.05)。3.奥硝唑在唾液中的分布符合三室模型,Cmax为7.05±1.36μg/mL,t1/2β为15.13±2.63h,AUC0-∞为80.58±17.2μg.h/ml,AUC0-t为68.26±13.79μg.h/ml;甲磺酸帕珠沙星在部分受试者唾液中的分布符合二室模型,Cmax为0.46±0.13μg/mL,t1/2β为1.21±1.03h,AUC0-∞为0.53±0.13μg.h/ml,AUC0-t为0.46±0.17μg.h/ml;头孢哌酮在唾液中的分布个体差异明显,无法得到良好的房室拟合模型。4.三种药物在龈沟液中的分布由于个体差异较大,无法得到良好的药代动力学模型拟合结果。结论:1.奥硝唑可以采用唾液药物浓度进行治疗药物监测。头孢哌酮、甲磺酸帕珠沙星不能采用唾液进行药物监测。2.龈沟液不能替代血液进行这三种抗生素的治疗药物监测。3.奥硝唑在唾液中的分布迅速、持久,在唾液、龈沟液中浓度均较高。头孢哌酮和甲磺酸帕珠沙星在唾液、龈沟液中浓度较低。
Orofacial infection is usually mixed infection of aerobic and anaerobic bacteria, the current antibiotics against those pathogenic bacterium include both wide-spectrum antibiotics and those which have strong antibacterial action specific against gram-positive and gram-negative bacillus or coccus. With the growing abuse of antibiotics, the drug adverse reaction and drug resistance are receiving more and more attention. Therapeutic drug monitoring is to messure the drug concentration in blood or other body fluid by morden analytical technology, providing the renferences for doctors to select and adjust drug regim, to prevent and decrease the drug adverse reaction and drug resistance. At present, some research have proved that persistent and predictable correlation exist between the saliva concentration and serum concentration for certain drugs, for these drugs, the saliva can replace serum to monitor the serum concentration, this method is simple, non-invasive, and easy for patient to accept. More and more researches have now focused on this area. Cefoperazone (CPZ), pazufloxacin (PAZ), ornidazole (ONZ) are three new antibiotics used against orofacial infection, their distribution in saliva and gingival crevicular fluid (GCF) remain unclear, furtherly it is still unknown whether saliva can be used to mornitor the drug concentration for these three antibiotics. Besides, the past research about the distribution of these drugs in GCF and drug serum concentration monitoring with GCF are scared, based on those status, this research aimed to investigate the distribution of CPZ, PAZ and ONZ in saliva, GCF and serum to determine the feasibility of monitoring drug serum concentration with saliva and GCF, the whole research have two parts:
The construction HPLC method for three antibiotics
Objective: To set up high-performance liquid chromatography (HPLC) method for detecting CPZ, PAZ and ONZ in saliva, GCF and serum. Method: Chromatography was carried out on a reversed-phase column (Agilent Zorbax SB-C_(18) ;5μm, 150mmx4.6mm) for CPZ and ONZ, Agilent Zorbax SB-C_(18) (5μm, 250mmx4.6mm) for PAZ. The mobile phase for CPZ consisted of acetonitrile and 0.02mol/L KH_2PO_4(1:6); the mobile phase for PAZ was a mixture of acetonitrile and 0.5% phosphoric acid containing 1% triethylamine (155:850); the mobile phase for ONZ was methanol-water (25:75). 20μl of the resulting solution was injected into the HPLC system at a flow rate of 1.0ml/ min, and the wavelength was seted at 254, 245 and 316 nm, respectively. The samples were deproteinised with acetonitrile, then extracted with methylene dichloride for CPZ; for PAZ, methanol was used to precipitate the impurity in the samples; samples were extracted with isopropanol-chloroform (5: 95) for ONZ. Results: The CPZ, PAZ and ORN in saliva and serum were separated on the baseline, the calibration curves showd favorable linear regression (r>0.999). The coefficients of variation for within-day and between-day performance were found to be all less than 5%; the recovery rates were all above 80%. Conclusion: The HPLC methods for messureing the concentration of cefoperazone, pazufloxacin and ornidazole had a high sensitivity, the precision and recovery rates were high and stable. These methods could be applied for the detections of these drugs in saliva, GCF and serum.
The distribution of three antibiotics in saliva and GCF
Objective: To observe the distribution of three antibiotics in saliva and GCF, and to determine the feasibility of monitoring serum drug concentration with saliva and GCF. Method: Twenty healthy volunteers were divided into three groups: 1) cefoperazone 1.5g; 2) pazufloxacin 0.3g; 3) ornidazole 0.6g, all the subjects were intervenously administrated antibiotics in 30 min. The concentrations of CPZ, PAZ and ONZ in saliva, GCF, and serum were assayed by HPLC, analysis of the correlation of the drug concentration in saliva or gingival crevicular fluid to that in serum was then performed. Results: 1. The concentration of ORN in saliva was strongly associated with plasma concentration (r=0.825～0.969), the ratio of saliva-to-plasma concentration (S/P) of ONZ was 0.99±0.13. The concentration of all the three antibiotics in GCF had no significant association with plasma concentration, both the concentration of CPZ and PAZ in saliva and GCF had no significant association with plasma concentration. 2. The distribution of all the three antibiotics in GCF could not achieve suitable compartment model because of obvious individual differences. 3. The Cmax of CPZ in samples decreased in order of serum (110.40±32.66μg/mL), GCF (38.98±29.23μg/mL), saliva (0.41±0.51μg/mL), for PAZ that is serum (9.46±3.38μg/mL), GCF (1.68±1.03μg/mL), saliva (0.40±0.13μg/mL), the Cmax of CPZ and PAZ in three samples were all significantly different (p<0.05); the highest Cmax of ONZ was in saliva (6.89±1.50μg/mL), next is serum (6.45±1.21μg/mL), the lowest was in GCF (5.61±1.24μg/mL). The distribution of ORN in saliva corresponded to three compartment model. The pharmacokinetic parameters were as follows: Cmax(7.05±1.36)μg/mL, t1/2β(15.13±2.63) h,AUC0-∞(80.58±17.2)μg.h/ml, AUCO-t (68.26±13.79)μg.h/ml; the distribution of PAZ in saliva of partial subjects corresponded to three compartment model, the pharmacokinetic parameters were as follows: Cmax(0.46±0.13μg/mL), t1/2β(1.21±1.03h), AUC0-∞(0.53±0.13μg.h/ml), AUC0-t(0.46±0.17μg.h/ml). For great individual differences of CPZ in saliva and GCF, no favorable compartment model could be achieved. Conclusion: 1. While ORN determined in saliva seems to be suitable for therapeutic drug monitoring, it could not be applied for CPZ and PAZ. 2. All the three antibiotics determined in GCF seems to be unsuitable for therapeutic drug monitoring. 3.ORN could rapidly distribute to saliva, and had highest concentration in saliva and relative longer elimination time, and the concentration of CPZ and PAZ in saliva and GCF were low.
引文
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