司帕沙星药代动力学研究
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摘要
目的:建立HPLC法检测生物样品中司帕沙星的药物浓度;研究家兔口服司帕沙星后体内药代动力学、眼内组织分布及其药代动力学;比较两种司帕沙星胶囊的人体生物等效性;并探讨司帕沙星人血浆蛋白结合率;为临床合理用药提供依据。
方法:(1)建立HPLC法检测生物样品中司帕沙星的药物浓度:采用Gemini Cl8柱(250mm×4.6mm,5μm),以加替沙星为内标,流动相磷酸二氢钾--三乙胺--甲醇,柱温30℃,流速1.2mL·min-1,检测波长为292nm,用二氯甲烷液-液萃取生物样品后进行HPLC检测分析。(2)6只家兔以12.4mg·kg-1灌服司帕沙星,不同时间点采集血液,高效液相色谱法测定血药浓度,采用3p97程序计算药动学参数。(3)27只家兔以12.4mg·kg-1灌服司帕沙星,不同时间点采集泪液、角膜、房水、虹膜-睫状体、晶状体、玻璃体标本,以高效液相色谱法测定眼内各组织中的药物浓度,用3p97程序计算药动学参数。(4)22名健康志愿受试者随机交叉单剂口服200mg司帕沙星试验制剂或参比制剂胶囊后,用高效液相色谱法测定血药浓度,3P97计算药动学参数,评价试验制剂与对照制剂的生物等效性。(5)采用平衡透析法结合HPLC法,对司帕沙星的人血浆蛋白结合率进行测定。
结果:司帕沙星在兔血浆内药-时曲线符合二室模型,Cmax为(4.79±0.39)μg·mL - 1 ; tmax为(3.80±0.45)h ; AUC0～t为(113.65±10.81)μg·h·mL-1;司帕沙星在泪液、角膜、房水、虹膜-睫状体、晶状体、玻璃体组织中Cmax分别为(13.75±1.36)μg·mL-1、(3.25±0.32)μg·g- 1、(2.06±0.14)μg·mL - 1、(3.41±0.26)μg·g - 1、(1.62±0.13)μg·g - 1、(2.18±0.18)μg·mL-1;tmax分别为(3.45±0.39)h、(2.58±0.56)h、(3.39±0.17)h、(3.04±0.78)h、(3.76±0.073)h、( 3.34±0.33 ) h ; AUC0～t分别为(118.68±5.64)μg·h·mL-1、(28.18±5.42)μg·h·g-1、(17.52±2.09)μg·h·mL-1、(36.77±10.47)μg·h·g-1、(16.12±0.59)μg·h·g-1、(16.57±0.47)μg·h·mL-1;司帕沙星试验制剂与参比制剂在人体内药时曲线符合二室模型,Cmax分别为(0.85±0.23)μg·mL - 1和(0.90±0.27)μg·mL - 1 , tmax分别为(5.59±2.28)h和(4.95±1.17)h,AUC0～t分别为(27.92±6.09)μg·h·mL-1和(29.65±8.49)μg·h·mL-1,相对生物利用度为(97.47±18.32)%;高、中、低3种浓度下,司帕沙星的血浆蛋白结合率分别为45.12%、45.52%、45.50%。
结论:HPLC法检测生物样品中司帕沙星的药物浓度。方法灵敏、简便、快速、重现性好,适用于生物样品药物浓度检测及药代动力学研究;司帕沙星家兔口服后吸收快,血药浓度较高,半衰期长;其在眼内各组织中分布广,浓度较高,可替代治疗眼病时肠外给药,方便可行;人体生物等效性试验结果,经方差分析和双单侧t检验(P>0.05),两种司帕沙星胶囊具有生物等效性。司帕沙星与人体血浆蛋白具有较强的结合。
OBJECTIVES:To explore a High Performance Liquid Chromatogra -phy (HPLC) method for the analysis of Sparfloxacin in biological samples. To study the pharmacokinetics(PK) of sparfloxacin after oral administration in rabbits.To study the distribution and pharmacokinetics of sparfloxacin in ocular tissues after oral administration in rabbits .To study bivequivalence of two kinds of sparfloxacin capsule.And get the plasma protein binding rate of SPFX. All of the researches will provide data for clinic prescription.
METHODS:(1)The analysis method of SPFX:The SPFX in biological samples were liquid liquid extraction (LLE) with dichlormethane. SPFX was separated on the Gemini Cl8 250mm×4.6mm,5μm column using potassium dihydrogen phosphate--triethylamine--methanol as the moblie phase(flow rate 1.2mL·min-1) and GFLX as the internal standard at 30℃with UV detector at wavelength 292nm. (2)Plasma samples were taken in different times after oral administration in 6 rabbits with 12.4mg·kg-1.The concentrations of the sparfloxacin were determined in plasma by HPLC . The pharmacokinetics parameters were calculated by 3p97.(3) Ocular tissues samples were taken in different times after oral administration in 27 rabbits with 12.4mg·kg-1.The concentrations of sparfloxacin in lacrimal fluid,cornea,aqueous humor,iris-ciliary body,lens and vitreous body were determined by HPLC. The pharmacokinetics parameters were calculated by 3p97.(4)A single dose of 200mg of sparfloxacin capsule was administered by randomized crossover way in 22 volunteers and the plasma concentrations of the sparfloxacin were determined by HPLC . The pharmacokinetic parameters were calculated with 3P97.Bivequivalence was evaluated . (5)The equilibrium dialysis combined with HPLC to determine the plasma concentration and plasma protein binding rate of SPFX was carried out.
RESULTS:The concentration-time curve of sparfloxacin fitted two compartment model. The peak plasma levels(Cmax) was(4.79±0.39)μg·mL- 1 ;the peak time(tmax) was (3.80±0.45)h; A UC0～t was (113.65±10.81)μg·h·mL- 1. The peak concentration of sparfloxacin in lacrimal fluid ,cornea, a queous humor ,i ris-ciliary body, l ens and vitreous body was (13.75±1.36)μg·mL - 1, (3.25±0.32)μg·g - 1, (2.06±0.14)μg·mL- 1,(3.41±0.26)μg·g -1 ,( 1.62±0.13)μg·g - 1,( 2.18±0.18)μg·mL- 1respectively;the half-life time in various tissues was (8.18±0.70)h ,( 9.94±3.90)h ,(5.05±0.66)h ,( 13.54±6.37)h, ( 5.67±1.15)h, ( 3.60±1.23)h respectively ;A UC0～t in various tissues was (118.68±5.64)μg·h·mL- 1 , (28.18±5.42)μg·h·g - 1,(17.52±2.09)μg·h·mL - 1,( 36.77±10.47)μg·h·g - 1, (16.12±0.59)μg·h·g- 1, (16.57±0.47)μg·h·mL- 1 respectively.The concentration-time curves of two preparations fitted two compartment model . The peak plasma levels (Cmax) were(0.85±0.23)μg·mL-1 and(0.90±0.27)μg·mL-1, respectively. The peak time(tmax) were(5.59±2.28)h and(4.95±1.17)h,respectively . AUC0～t were (27.92±6.09)μg·h·mL- 1 and (29.65±8.49)μg·h·mL- 1 ,respectively . The relative bioavailabitity of sparfloxacin capsule was (97.47±18.32)%.The plasma protein binding rates of SPFX at low,middle and high concentrations were 45.12% ,45.52% and 45.50% respectively.
Conclusion:The method for the determination of SPFX in biological samples was sensitive,simple,rapid and good reproduction.It can be used to determine the concentration of SPFX in the biological samples and study the pharmacokinetics(PK) parameters of it.Sparfloxacin has a high concentration in blood of rabbits after oral administration. The half time is long.SPFX has a good distribution and high concentration in various intraocular tissues of rabbit after oarl administration. It can replace parenteral sparfloxacin for ophthalmic diseases.The result of two one-sided t tests ( P> 0.05 )suggest that the test is bivequivalence with the reference.SPFX has high binding power with plasma protein.
方法:(1)建立HPLC法检测生物样品中司帕沙星的药物浓度:采用Gemini Cl8柱(250mm×4.6mm,5μm),以加替沙星为内标,流动相磷酸二氢钾--三乙胺--甲醇,柱温30℃,流速1.2mL·min-1,检测波长为292nm,用二氯甲烷液-液萃取生物样品后进行HPLC检测分析。(2)6只家兔以12.4mg·kg-1灌服司帕沙星,不同时间点采集血液,高效液相色谱法测定血药浓度,采用3p97程序计算药动学参数。(3)27只家兔以12.4mg·kg-1灌服司帕沙星,不同时间点采集泪液、角膜、房水、虹膜-睫状体、晶状体、玻璃体标本,以高效液相色谱法测定眼内各组织中的药物浓度,用3p97程序计算药动学参数。(4)22名健康志愿受试者随机交叉单剂口服200mg司帕沙星试验制剂或参比制剂胶囊后,用高效液相色谱法测定血药浓度,3P97计算药动学参数,评价试验制剂与对照制剂的生物等效性。(5)采用平衡透析法结合HPLC法,对司帕沙星的人血浆蛋白结合率进行测定。
结果:司帕沙星在兔血浆内药-时曲线符合二室模型,Cmax为(4.79±0.39)μg·mL - 1 ; tmax为(3.80±0.45)h ; AUC0～t为(113.65±10.81)μg·h·mL-1;司帕沙星在泪液、角膜、房水、虹膜-睫状体、晶状体、玻璃体组织中Cmax分别为(13.75±1.36)μg·mL-1、(3.25±0.32)μg·g- 1、(2.06±0.14)μg·mL - 1、(3.41±0.26)μg·g - 1、(1.62±0.13)μg·g - 1、(2.18±0.18)μg·mL-1;tmax分别为(3.45±0.39)h、(2.58±0.56)h、(3.39±0.17)h、(3.04±0.78)h、(3.76±0.073)h、( 3.34±0.33 ) h ; AUC0～t分别为(118.68±5.64)μg·h·mL-1、(28.18±5.42)μg·h·g-1、(17.52±2.09)μg·h·mL-1、(36.77±10.47)μg·h·g-1、(16.12±0.59)μg·h·g-1、(16.57±0.47)μg·h·mL-1;司帕沙星试验制剂与参比制剂在人体内药时曲线符合二室模型,Cmax分别为(0.85±0.23)μg·mL - 1和(0.90±0.27)μg·mL - 1 , tmax分别为(5.59±2.28)h和(4.95±1.17)h,AUC0～t分别为(27.92±6.09)μg·h·mL-1和(29.65±8.49)μg·h·mL-1,相对生物利用度为(97.47±18.32)%;高、中、低3种浓度下,司帕沙星的血浆蛋白结合率分别为45.12%、45.52%、45.50%。
结论:HPLC法检测生物样品中司帕沙星的药物浓度。方法灵敏、简便、快速、重现性好,适用于生物样品药物浓度检测及药代动力学研究;司帕沙星家兔口服后吸收快,血药浓度较高,半衰期长;其在眼内各组织中分布广,浓度较高,可替代治疗眼病时肠外给药,方便可行;人体生物等效性试验结果,经方差分析和双单侧t检验(P>0.05),两种司帕沙星胶囊具有生物等效性。司帕沙星与人体血浆蛋白具有较强的结合。
OBJECTIVES:To explore a High Performance Liquid Chromatogra -phy (HPLC) method for the analysis of Sparfloxacin in biological samples. To study the pharmacokinetics(PK) of sparfloxacin after oral administration in rabbits.To study the distribution and pharmacokinetics of sparfloxacin in ocular tissues after oral administration in rabbits .To study bivequivalence of two kinds of sparfloxacin capsule.And get the plasma protein binding rate of SPFX. All of the researches will provide data for clinic prescription.
METHODS:(1)The analysis method of SPFX:The SPFX in biological samples were liquid liquid extraction (LLE) with dichlormethane. SPFX was separated on the Gemini Cl8 250mm×4.6mm,5μm column using potassium dihydrogen phosphate--triethylamine--methanol as the moblie phase(flow rate 1.2mL·min-1) and GFLX as the internal standard at 30℃with UV detector at wavelength 292nm. (2)Plasma samples were taken in different times after oral administration in 6 rabbits with 12.4mg·kg-1.The concentrations of the sparfloxacin were determined in plasma by HPLC . The pharmacokinetics parameters were calculated by 3p97.(3) Ocular tissues samples were taken in different times after oral administration in 27 rabbits with 12.4mg·kg-1.The concentrations of sparfloxacin in lacrimal fluid,cornea,aqueous humor,iris-ciliary body,lens and vitreous body were determined by HPLC. The pharmacokinetics parameters were calculated by 3p97.(4)A single dose of 200mg of sparfloxacin capsule was administered by randomized crossover way in 22 volunteers and the plasma concentrations of the sparfloxacin were determined by HPLC . The pharmacokinetic parameters were calculated with 3P97.Bivequivalence was evaluated . (5)The equilibrium dialysis combined with HPLC to determine the plasma concentration and plasma protein binding rate of SPFX was carried out.
RESULTS:The concentration-time curve of sparfloxacin fitted two compartment model. The peak plasma levels(Cmax) was(4.79±0.39)μg·mL- 1 ;the peak time(tmax) was (3.80±0.45)h; A UC0～t was (113.65±10.81)μg·h·mL- 1. The peak concentration of sparfloxacin in lacrimal fluid ,cornea, a queous humor ,i ris-ciliary body, l ens and vitreous body was (13.75±1.36)μg·mL - 1, (3.25±0.32)μg·g - 1, (2.06±0.14)μg·mL- 1,(3.41±0.26)μg·g -1 ,( 1.62±0.13)μg·g - 1,( 2.18±0.18)μg·mL- 1respectively;the half-life time in various tissues was (8.18±0.70)h ,( 9.94±3.90)h ,(5.05±0.66)h ,( 13.54±6.37)h, ( 5.67±1.15)h, ( 3.60±1.23)h respectively ;A UC0～t in various tissues was (118.68±5.64)μg·h·mL- 1 , (28.18±5.42)μg·h·g - 1,(17.52±2.09)μg·h·mL - 1,( 36.77±10.47)μg·h·g - 1, (16.12±0.59)μg·h·g- 1, (16.57±0.47)μg·h·mL- 1 respectively.The concentration-time curves of two preparations fitted two compartment model . The peak plasma levels (Cmax) were(0.85±0.23)μg·mL-1 and(0.90±0.27)μg·mL-1, respectively. The peak time(tmax) were(5.59±2.28)h and(4.95±1.17)h,respectively . AUC0～t were (27.92±6.09)μg·h·mL- 1 and (29.65±8.49)μg·h·mL- 1 ,respectively . The relative bioavailabitity of sparfloxacin capsule was (97.47±18.32)%.The plasma protein binding rates of SPFX at low,middle and high concentrations were 45.12% ,45.52% and 45.50% respectively.
Conclusion:The method for the determination of SPFX in biological samples was sensitive,simple,rapid and good reproduction.It can be used to determine the concentration of SPFX in the biological samples and study the pharmacokinetics(PK) parameters of it.Sparfloxacin has a high concentration in blood of rabbits after oral administration. The half time is long.SPFX has a good distribution and high concentration in various intraocular tissues of rabbit after oarl administration. It can replace parenteral sparfloxacin for ophthalmic diseases.The result of two one-sided t tests ( P> 0.05 )suggest that the test is bivequivalence with the reference.SPFX has high binding power with plasma protein.
引文
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