甲磺酸加替沙星胶囊的人体药代动力学及生物等效性评价
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摘要
目的：
甲磺酸加替沙星胶囊是我国科技工作者研制的国家4类新药，为明确其在人体内的吸收、分布、代谢及排泄规律，本实验对其进行了人体药代动力学研究，同时对其与甲磺酸加替沙星片剂进行生物等效性评价，为指导临床安全、合理的用药提供科学理论依据。
方法：
本研究分三部分：第一部分是建立检测血清中加替沙星浓度的分析方法学；第二部分研究甲磺酸加替沙星片剂在健康人体的药代动力学；第三部分为甲磺酸加替沙星胶囊与片剂的人体生物等效性评价。
1．检测血浆中加替沙星浓度分析方法学的建立：
建立以HPLC测定血浆中加替沙星浓度的分析方法学；流速为1ml／min，流动相为甲醇：水；十二烷基硫酸钠=500ml：500ml：0.35g(pH=0.3)，检测波长为292nm。通过对日内、日间精密度、方法回收率、提取回收率、线性范围确定、定量限、
选择性等效能指标的考核对方法学进行评价。
2.甲磺酸加替沙星胶囊与片剂在健康人体的药代动力学研究:
本实验经国家药监局批准、第四军医大学西京医院药事伦理
委员会成员一致通过、与18名男性健康志愿者签定知情同意书后
开始。志愿者年龄18一40岁，体重(60.8士7.6)kg，身高(169.6士3.5)em;
血、尿常规、肝功、’肾功及心电图检查均正常，无消化系统及药
物过敏史。试验前及实验期间未服用其他任何药物。18位志愿者
于实验前晚19:oo后开始禁食，次晨收集服药前静脉血5ml，分
两次实验用24Oml温开水单剂量口服甲磺酸加替沙星胶囊和片剂
各400 mg，随收集服药后0.25、0.5、0.75、1、1.5、2、3、4、6、
8、12和24h的静脉血5ml置加肝素的抗凝管中，为避免饮食、
饮水及睡眠影响药物在机体内的代谢，服药4h内禁止饮食、睡觉，
2h内禁止饮水，受试者的午餐、饮食、饮水均是按照固定的时间
表来安排，期间禁烟酒、咖啡、茶水。将血浆样品在常温下以105009
高速离心smin，将分离后血浆放置在一20℃的环境中待测，整个实
验期间配备有经验的医生、护士监护。
采用外标法用HPLC测定血浆样品中的加替沙星浓度。Tmax、
cma、采用实测值，应用梯形法计算AUC(。一24h，和AUC(。一哟;以药-
时曲线消除相的浓度取对数后对时间进行回归，其直线斜率即为
消除速率常数Ke，根据公式Tl/2 Ke=0.693服e求得Tl/2 Ke。应用中
国数学药理学会的3P97药代动力学统计学软件计算MRT(。_24h)和
AUC(o一ao)o
3.甲磺酸加替沙星胶囊和片剂在人体的相对生物等效性评价:
采用两阶段随机交叉一自身对照实验设计方案，将18名男性
健康志愿者随机分为A、B两组，实验前晚19:00开始禁食，于
次日晨7:50先采集空腹血sml作对照，10min后A组用240 ml
温开水口服甲磺酸加替沙星胶囊，B组口服甲磺酸加替沙星片剂，
均为400 mg，收集服药后0.25、0.5、0.75、一、一5、2、3、4、6、
8、12和24h的静脉血各smL，置于加肝素抗凝管中，处理方法
及实验期间注意事项同第二部分实验;经lwk清洗期后交叉换服
药，程序方法同上。
用HPLC测定血浆中加替沙星的浓度。Tmax、Cma、采用实测
值，应用中国数学药理学会的3P97统计学软件，计算两药各自的
AUC、T，/2 Ke和MRT，将两种制剂的Tma、和经对数转换后的AUC
(0_24h)和Cma、分别进行方差分析、双单侧t检验以及90%置信区
间的等效性统计学分析。
结果:
1.本实验条件下，HPLC的理论塔板数为7408，柱效良好。血浆
中药物和基线分离良好且选择性高，在血药浓度0.巧一9.92mg’L一‘
范围内以加替沙星浓度(C)对峰面积(A)回归，得到加替沙星
回归方程为c=2.973xlo一6A一0.0722(r一0.9993，n=6)，浓度与峰面
积相关性良好(二0.9993)，血浆中加替沙星的最低检出浓度(按
信噪比习计)为Zong·mL，。血浆高(4.96 mg·L一，)、中(1.24 mg·L一‘)、
低(0 .31mg’L一‘)浓度下的日内变异系数分别为1.02%、1.75%、
5.56%;日间变异系数分别为7.34%、3.47%、1.64%;方法回收率
分别为(96.4肚2.41)%、(96.54士1.94)%、(97.21士1.25)%;提取回收
率分别为(90.96士1 .05)%、(90.50士1.96)%和(91.48士2.74)%。冻融实
验后前浓度比值平均为99.97%。
2.甲磺酸加替沙星胶囊与片剂单剂量400mg给18名男性健康受
试者口服后，其药代动力学参数分别为Tma、:1 .51士O39h和
1 .54士o.4oh;ema、:3.45士0.54 mg·L一‘和3，43士0.96 mg·L一‘;刘e
(o一24h。:34.5一士8.49 mg·h·L一l和33.04士一0.25 mg·h·LI，TlzZke:6.334
士0 .668h和6.608士0.977h;MRT(o一in。:9.562士0.863h和
9 .697士1.067h;AUC(。一in。:37.394士9.172 mg·h·L一’和35.907土一。，572
mg·h·L一l。
3.采用双周期随机一自身对照实验设计方案，将18名健康志愿
者随机分两组分别口服甲磺酸加替沙星的胶囊和片剂400mg后，
测定其相应药代动力学参数，将Tma、和取对数后的Cma、、AUC〔o_24h)
经统计学的方差分析、单双侧t检验以及90%置信区间分析，拒
绝接受二者不等效的假设(P>0.05);且试验制剂与参比制剂之间
的个体间、制剂间、周期间均无显著性差异(
Gatifloxacin mesylate capsule is the new formulation of gatifloxacin made in. china. The study aimed to definite its pharmacokinetical charicateristic such as absorption, disposion, metablism and excretion in healthy body, and to evaluate the bioequivalence between gatifloxacin mesylate capsules and tablets to provide scientifical evidence in order to direct safe and reasonable appalication on clinic. METHODS
The study was divided into three parts. The first was to set up the analytic methodology; and the second mainly studied the pharmacokinetics of gatifloxacin mesylate capsules and tablets in body of healthy volunteers; the third studied the bioequivalence of gatifloxacin mesylate capsules and tablets in healthy volunteers . 1. Set up the analytic methodology:
An HPLC method with high precision, high paricularity and sensibility was developed and validated for gatifloxacin assay in plasma samples. The mobile phase consisted of 500ml methanol,
500ml water (50/50,v/v) and 3.5g dodecyl sodium sulfate (pH=3.0) .The flow rate was 1.0ml min-1 and the effect was monitored ' at 292nm. Under these conditions, the retention time of gatifloxacin was 4.84min. To evaluate the methonology by detecting the limit of quantitation for gatifloxacin in plasma, method recovery rate, draw recovery rate, RSD of inter-precision and intra-precision, selectivity and ruggedness to prove whether it could be use to study the pharmacokinetics and bioequivalence of gatifloxacin mesylate or not.
2. Pharmacokinetics of Gatifloxacin mesylate capsules and Gatifloxacin mesylate tablets in healthy volunteers:
Prior to trial initiation, the study protocol was approved by the Nation and the Ethic Committee of Xijing Hospital of the Fourth Military Medical University, Xi'an, Shaanxi. The 18 subjectes were informed about the study procedures and signed the informed consent form after explaining the purpose of the study. After an overnight fasting, all volunteers were given single dose of gatifloxacin mesylate capsules and gatifloxacin mesylate tablets 400 mg with 240ml of water in two times. No food was allowed until 4h after dose . administration. Water intake as allowed after 2h of dose; water, lunch and dinner were given to all volunteers according to a time schedule. They were not permitted to lie down or to sleep for the first 4h after the dose. Approximately 5ml of blood samples for Gatifloxacin mesylate assay were drawn before (Oh) and at 0.25, 0.5, 0.75, 1, 1.5, 2,
3, 4, 6, 8, 12 and 24h after the dose. The blood samples were centrifuged at 10500g for 8 min at room temperature; plasma was separated and kept frozen at -20 until assayed. 100 L were injected into the HPLC system with external-standard method. The Tmax and. Cmax were actual value, and calculated the AUC (0-2-4h) and
AUC(0-inf)by echelon methods; the elimination rate constant (Ke) was obtained from the least-square fitted terminal log-linear portion of the plasma concentration- time profile. The elimination half-life (T1/2) was calculated as 0.693/ Ke. MRT(o-24h) and MRT(0-inf) by pharmacokinetic statistical software of 3P97.
3. Bioequivalance of Gatifloxacin mesylate tablets and Gatifloxacin mesylate capsules in healthy volunteers:
This study was based on a single dose, randomized, two-treatment, two-period crossover design. 18 volunteers were divided into two groups that A and B, In the morning of phase I , after an overnight fasting volunteers were given single dose of gatifloxacin mesylate capsules and gatifloxacin mesylate tablets 400 mg with 240ml of water respectively. Attention in the experience was the same as the second part. Approximately 5ml of blood samples for gatifloxacin mesylate assay were drawn before (Oh) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24h after the dose. The blood samples were centrifuged at 10500 x g for 8 min at room temperature; plasma was separated and kept frozen at -20 until assayed. After a washout period of 7d the study was repeated in the same manner to complete the crossover design. The g
甲磺酸加替沙星胶囊是我国科技工作者研制的国家4类新药，为明确其在人体内的吸收、分布、代谢及排泄规律，本实验对其进行了人体药代动力学研究，同时对其与甲磺酸加替沙星片剂进行生物等效性评价，为指导临床安全、合理的用药提供科学理论依据。
方法：
本研究分三部分：第一部分是建立检测血清中加替沙星浓度的分析方法学；第二部分研究甲磺酸加替沙星片剂在健康人体的药代动力学；第三部分为甲磺酸加替沙星胶囊与片剂的人体生物等效性评价。
1．检测血浆中加替沙星浓度分析方法学的建立：
建立以HPLC测定血浆中加替沙星浓度的分析方法学；流速为1ml／min，流动相为甲醇：水；十二烷基硫酸钠=500ml：500ml：0.35g(pH=0.3)，检测波长为292nm。通过对日内、日间精密度、方法回收率、提取回收率、线性范围确定、定量限、
选择性等效能指标的考核对方法学进行评价。
2.甲磺酸加替沙星胶囊与片剂在健康人体的药代动力学研究:
本实验经国家药监局批准、第四军医大学西京医院药事伦理
委员会成员一致通过、与18名男性健康志愿者签定知情同意书后
开始。志愿者年龄18一40岁，体重(60.8士7.6)kg，身高(169.6士3.5)em;
血、尿常规、肝功、’肾功及心电图检查均正常，无消化系统及药
物过敏史。试验前及实验期间未服用其他任何药物。18位志愿者
于实验前晚19:oo后开始禁食，次晨收集服药前静脉血5ml，分
两次实验用24Oml温开水单剂量口服甲磺酸加替沙星胶囊和片剂
各400 mg，随收集服药后0.25、0.5、0.75、1、1.5、2、3、4、6、
8、12和24h的静脉血5ml置加肝素的抗凝管中，为避免饮食、
饮水及睡眠影响药物在机体内的代谢，服药4h内禁止饮食、睡觉，
2h内禁止饮水，受试者的午餐、饮食、饮水均是按照固定的时间
表来安排，期间禁烟酒、咖啡、茶水。将血浆样品在常温下以105009
高速离心smin，将分离后血浆放置在一20℃的环境中待测，整个实
验期间配备有经验的医生、护士监护。
采用外标法用HPLC测定血浆样品中的加替沙星浓度。Tmax、
cma、采用实测值，应用梯形法计算AUC(。一24h，和AUC(。一哟;以药-
时曲线消除相的浓度取对数后对时间进行回归，其直线斜率即为
消除速率常数Ke，根据公式Tl/2 Ke=0.693服e求得Tl/2 Ke。应用中
国数学药理学会的3P97药代动力学统计学软件计算MRT(。_24h)和
AUC(o一ao)o
3.甲磺酸加替沙星胶囊和片剂在人体的相对生物等效性评价:
采用两阶段随机交叉一自身对照实验设计方案，将18名男性
健康志愿者随机分为A、B两组，实验前晚19:00开始禁食，于
次日晨7:50先采集空腹血sml作对照，10min后A组用240 ml
温开水口服甲磺酸加替沙星胶囊，B组口服甲磺酸加替沙星片剂，
均为400 mg，收集服药后0.25、0.5、0.75、一、一5、2、3、4、6、
8、12和24h的静脉血各smL，置于加肝素抗凝管中，处理方法
及实验期间注意事项同第二部分实验;经lwk清洗期后交叉换服
药，程序方法同上。
用HPLC测定血浆中加替沙星的浓度。Tmax、Cma、采用实测
值，应用中国数学药理学会的3P97统计学软件，计算两药各自的
AUC、T，/2 Ke和MRT，将两种制剂的Tma、和经对数转换后的AUC
(0_24h)和Cma、分别进行方差分析、双单侧t检验以及90%置信区
间的等效性统计学分析。
结果:
1.本实验条件下，HPLC的理论塔板数为7408，柱效良好。血浆
中药物和基线分离良好且选择性高，在血药浓度0.巧一9.92mg’L一‘
范围内以加替沙星浓度(C)对峰面积(A)回归，得到加替沙星
回归方程为c=2.973xlo一6A一0.0722(r一0.9993，n=6)，浓度与峰面
积相关性良好(二0.9993)，血浆中加替沙星的最低检出浓度(按
信噪比习计)为Zong·mL，。血浆高(4.96 mg·L一，)、中(1.24 mg·L一‘)、
低(0 .31mg’L一‘)浓度下的日内变异系数分别为1.02%、1.75%、
5.56%;日间变异系数分别为7.34%、3.47%、1.64%;方法回收率
分别为(96.4肚2.41)%、(96.54士1.94)%、(97.21士1.25)%;提取回收
率分别为(90.96士1 .05)%、(90.50士1.96)%和(91.48士2.74)%。冻融实
验后前浓度比值平均为99.97%。
2.甲磺酸加替沙星胶囊与片剂单剂量400mg给18名男性健康受
试者口服后，其药代动力学参数分别为Tma、:1 .51士O39h和
1 .54士o.4oh;ema、:3.45士0.54 mg·L一‘和3，43士0.96 mg·L一‘;刘e
(o一24h。:34.5一士8.49 mg·h·L一l和33.04士一0.25 mg·h·LI，TlzZke:6.334
士0 .668h和6.608士0.977h;MRT(o一in。:9.562士0.863h和
9 .697士1.067h;AUC(。一in。:37.394士9.172 mg·h·L一’和35.907土一。，572
mg·h·L一l。
3.采用双周期随机一自身对照实验设计方案，将18名健康志愿
者随机分两组分别口服甲磺酸加替沙星的胶囊和片剂400mg后，
测定其相应药代动力学参数，将Tma、和取对数后的Cma、、AUC〔o_24h)
经统计学的方差分析、单双侧t检验以及90%置信区间分析，拒
绝接受二者不等效的假设(P>0.05);且试验制剂与参比制剂之间
的个体间、制剂间、周期间均无显著性差异(
Gatifloxacin mesylate capsule is the new formulation of gatifloxacin made in. china. The study aimed to definite its pharmacokinetical charicateristic such as absorption, disposion, metablism and excretion in healthy body, and to evaluate the bioequivalence between gatifloxacin mesylate capsules and tablets to provide scientifical evidence in order to direct safe and reasonable appalication on clinic. METHODS
The study was divided into three parts. The first was to set up the analytic methodology; and the second mainly studied the pharmacokinetics of gatifloxacin mesylate capsules and tablets in body of healthy volunteers; the third studied the bioequivalence of gatifloxacin mesylate capsules and tablets in healthy volunteers . 1. Set up the analytic methodology:
An HPLC method with high precision, high paricularity and sensibility was developed and validated for gatifloxacin assay in plasma samples. The mobile phase consisted of 500ml methanol,
500ml water (50/50,v/v) and 3.5g dodecyl sodium sulfate (pH=3.0) .The flow rate was 1.0ml min-1 and the effect was monitored ' at 292nm. Under these conditions, the retention time of gatifloxacin was 4.84min. To evaluate the methonology by detecting the limit of quantitation for gatifloxacin in plasma, method recovery rate, draw recovery rate, RSD of inter-precision and intra-precision, selectivity and ruggedness to prove whether it could be use to study the pharmacokinetics and bioequivalence of gatifloxacin mesylate or not.
2. Pharmacokinetics of Gatifloxacin mesylate capsules and Gatifloxacin mesylate tablets in healthy volunteers:
Prior to trial initiation, the study protocol was approved by the Nation and the Ethic Committee of Xijing Hospital of the Fourth Military Medical University, Xi'an, Shaanxi. The 18 subjectes were informed about the study procedures and signed the informed consent form after explaining the purpose of the study. After an overnight fasting, all volunteers were given single dose of gatifloxacin mesylate capsules and gatifloxacin mesylate tablets 400 mg with 240ml of water in two times. No food was allowed until 4h after dose . administration. Water intake as allowed after 2h of dose; water, lunch and dinner were given to all volunteers according to a time schedule. They were not permitted to lie down or to sleep for the first 4h after the dose. Approximately 5ml of blood samples for Gatifloxacin mesylate assay were drawn before (Oh) and at 0.25, 0.5, 0.75, 1, 1.5, 2,
3, 4, 6, 8, 12 and 24h after the dose. The blood samples were centrifuged at 10500g for 8 min at room temperature; plasma was separated and kept frozen at -20 until assayed. 100 L were injected into the HPLC system with external-standard method. The Tmax and. Cmax were actual value, and calculated the AUC (0-2-4h) and
AUC(0-inf)by echelon methods; the elimination rate constant (Ke) was obtained from the least-square fitted terminal log-linear portion of the plasma concentration- time profile. The elimination half-life (T1/2) was calculated as 0.693/ Ke. MRT(o-24h) and MRT(0-inf) by pharmacokinetic statistical software of 3P97.
3. Bioequivalance of Gatifloxacin mesylate tablets and Gatifloxacin mesylate capsules in healthy volunteers:
This study was based on a single dose, randomized, two-treatment, two-period crossover design. 18 volunteers were divided into two groups that A and B, In the morning of phase I , after an overnight fasting volunteers were given single dose of gatifloxacin mesylate capsules and gatifloxacin mesylate tablets 400 mg with 240ml of water respectively. Attention in the experience was the same as the second part. Approximately 5ml of blood samples for gatifloxacin mesylate assay were drawn before (Oh) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24h after the dose. The blood samples were centrifuged at 10500 x g for 8 min at room temperature; plasma was separated and kept frozen at -20 until assayed. After a washout period of 7d the study was repeated in the same manner to complete the crossover design. The g
引文
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