Ⅰ类新药艾普拉唑的临床药物代谢动力学研究
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摘要
Ⅰ类新药艾普拉唑是丽珠制药公司研发的新一代强效质子泵抑制剂,它是治疗胃肠道相关疾病的抑酸剂。本文是研究艾普拉唑的测定方法、艾普拉唑代谢产物、艾普拉唑的药代动力学以及抗幽门螺杆菌三联用药方案对艾普拉唑和克拉红霉素药物代谢动力学的影响等四个方面。
一、液相色谱-串联质谱法测定血浆中艾普拉唑及其代谢产物及在药代动力学上的应用
目的：建立快速、灵敏的液相色谱-串联质谱法测定人血浆中的艾普拉唑及其代谢产物,用于受试者口服艾普拉唑后的药代动力学研究。
方法：选用Thermo HyPURITYC18柱,流动相为10mM甲酸胺水溶液：乙腈(50：50),柱温30度,三重四极杆质谱以多反应监测方式进行检测,检测的离子：艾普拉唑m/z367.2→184.0；艾普拉唑砜：m／z：383.3→184.1；艾普拉唑硫醚：m／z：351.2→168.1；内标奥美拉唑：m／z：346.2→198.0。12名健康受试者分别口服5mg的艾普拉唑肠溶片在0-48h采血,用建立的LC-MS/MS方法检测其体内艾普拉唑及其两个代谢产物的血药浓度。
结果：其线性范围艾普拉唑为0.23-2400.00 ng/mL;艾普拉唑砜为0.05-105.00 ng/mL;艾普拉唑硫醚为0.06-45.00ng/mL。LLOQ分别为0.23、0.05和0.06ng/mL。结论：该方法灵敏度高,实用性强,适用于临床药物动力学研究。
二、人尿中艾普拉唑代谢物的结构鉴定
目的：利用LC-MS/MS和LC-NMR鉴定口服艾普拉唑在人尿中的四种代谢产物
方法：尿样在被Na2CO3溶液(1 mol/L)碱化后,加入适量二氯甲烷以及0.05 mol/L的醋酸铵缓冲溶液进行萃取。选用伊利特C18柱,流动相为甲醇：0.05MNH4AC水溶液,Agilent 1200色谱系统进行检测。
结果：通过HPLC-MS/MS以及HPLC-NMR实验鉴定了健康受试者服用艾普拉唑后尿液中的代谢产物M1-M4。4个代谢产物均为艾普拉唑的醚化产物,艾普拉唑硫醚,12-羟基艾普拉唑硫醚,11,12-二羟基硫醚和艾普拉唑硫醚A。由此,我们推断4个代谢产物的代谢途径为：艾普拉唑首先被代谢酶还原成艾普拉唑硫醚(M1),艾普拉唑硫醚(M1)接着被还原成艾普拉唑硫醚A(M4)以及发生羟基化反应生成12-羟基艾普拉唑硫醚(M2),12-羟基艾普拉唑硫醚(M2)再次发生羟基化反应生成11,12-二羟基艾普拉唑硫醚(M3)。此外,在尿液中未检测到原料药、砜化产物以及去甲基化和羟基化的产物。
三、在中国健康人中研究新型质子泵抑制剂艾普拉唑与CYP3A5和CYP2C19基因型相关的药代动力学
目的：本试验是研究新型质子泵抑制剂艾普拉唑在健康中国受试者中的药代动力学以及和代谢酶CYP3A5和CYP2C19的基因多态性。
方法：在202名健康中国受试者中筛选CYP3A5*3基因型,根据他们的CYP3A5和CYP2C19基因型有21名成年男子入选参加本实验。
在服用单剂量艾普拉唑后利用LC-MS/MS检测艾普拉唑和代谢产物在血浆中的血药浓度。
结果：在CYP2C19野生纯合子及突变杂合子中即所有的受试者中,艾普拉唑和艾普拉唑砜的主要代谢参数在3组CYP3A5基因型中显著变化。虽然CYP3A5高表达(CYP3A5*1／*1)显示比低表达(CYP3A5*1/*3)较高的清除率,但是无表达(CYP3A5*3／*3)在3组不同基因型中有最高的清除率。根据这一结果,可以认为CYP3A5*1／*1、CYP3A5*1/*3、CYP3A5*3／*3,代谢艾普拉唑的能力分别为中、低、高。这一结果提示我们CYP3A5酶活性与艾普拉唑的代谢无关。假如在3组基因型中,CYP3A5基因型-表型与总CYP3A酶活性没有我们预期的相关性,我们就不能用CYP3A5基因型代表总的CYP3A活性。从而得出结论本试验没有发现CYP3A5于艾普拉唑的代谢有相关性。
四、抗幽门螺杆菌三联用药方案对艾普拉唑药物代谢动力学的影响
目的：三联用药方案中多剂量艾普拉唑和非联用方案中多剂量艾普拉唑药代动力学参数差异的研究
方法：本研究为自身前后对照、双周期、双交叉实验。第一阶段连续服用艾普拉唑5 mg Bid×6天。第一天和第七天抽取服药后0,0.5,1,1.5,2,3,4,6,8,12,24,48和72小时的5 ml血样(采用静脉留滞针)和收集服药后0-24小时分段尿。一周洗脱期后开始第二阶段连续服用克拉霉素500 mg Bid+阿莫西林1 g Bid+消旋艾普拉唑5 mg Bid三联用药×6天。抽取相同时间点8 ml血样(采用静脉留滞针)。两组受试者经洗脱期后交换服药方式,采集相应时间点的血药浓度。采用HPLC-MS/MS法测定给药后不同时间艾普拉唑血药浓度,利用DAS Ver2.0计算药动学参数和进行统计分析。
结果：三联用药组艾普拉唑在吸收速度和吸收量上均较单剂量艾普拉唑组降低,代谢产物之一艾普拉唑砜在吸收速度和吸收量上均较单剂量艾普拉唑组降低,而代谢产物艾普拉唑硫醚在吸收速度和吸收量上均较单剂量艾普拉唑组增高。
Ilaprazole is a new proton pump inhibitor designed for the treatment of gastric ulcers. Our study consists of four parts, determination of ilapraozle and its two metabolites in human plasma by LC-MS/MS, Identification of ilaprazole urinary metabolites in human by high-performance liquid chromatography -tandem mass spectrometry and stopped-flow high-performance liquid chromatography-nuclear magnetic resonance experiments, pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes and the effect of standard Triple-Drug therapy for helicobacter pylori eradication on the pharmacokinetcs of Ilaprazole.
Part 1. Determination of ilapraozle and its two metabolites in human plasma by LC-MS/MS
An analytical method based on liquid chromatography and electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) has been improved and validated for the quantitative measurement of ilaprazole and it's two metablites in human plasma. Separation of analytes and the internal standard (IS) omeprazole was performed on a Thermo HyPURITY C18 column (150x2. 1mm,5μm) with a mobile phase consisting of 10mM ammonium formate water solution- acetonitrile (50:50,v/v) at a flow rate of 0.25 mL/min. The API4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring mode via positive electrospray ionization interface using the transition m/z 367.2→m/z184.0 for ilaprazole, m/z 383.3→m/z 184.1 for ilaprazole sulfone, m/z 351.2→m/z168.1 for ilaprazole thiol ether and m/z 346.2→m/z 198.0 for omeprazole. The method was linear over the concentration range of 0.23 - 2400.00 ng/mL for ilaprzole,0.05-105.00 ng/mL for ilaprazole thiol ether and 0.06 - 45.00 ng/mL for ilaprazole sulfone, respectively. The intra- and inter- day prcisions were all less than 15% in terms of relative standard deviation (R.S.D), and the accuracy was within 15% in terms of relative error (R.E) for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.23,0.05 and 0.06 ng/mL with acceptable precision and accuracy for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether, respectively. The validated method offered sensitivity and wide linear concentration range. This method was successfully applied for the evaluation of pharmacokinetics of ilaprazole and it's two metablites after single oral doses of 5 mg ilaprazole to 12 Chinese healthy volunteers.
Part 2. Identification of ilaprazole urinary metabolites in human by high-performance liquid chromatography -tandem mass spectrometry and stopped-flow high-performance liquid chromatography-nuclear magnetic resonance experiments
The structural elucidation of ilaprazole metabolites in human urine was described by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and stopped-flow liquid chromatography-nuclear magnetic resonance (HPLC-NMR) experiments. Urinary samples were precipitated by sodium carbonate solution, and then extracted by liquid-liquid extraction with methyl chloride after adding ammonium acetate buffer. The enriched sample was separated using a C18 reversed-phase column with the mobile phase composed of acetonitrile and 0.05 mol/l ammonium acetate buffer in a gradient solution, and then directly coupled MS/MS detection in an on-line mode or 1H-NMR (500 MHz) spectroscopic detection in a stopped-flow mode. Four sulfide metabolites, ilaprazole sulfide,12-hydroxy-ilaprazole sulfide,11,12-dihydroxy-ilaprazole sulfide and ilaprazole sulfide A were identified from the combined MS/MS and NMR data with those of the parent drug and available standard without actually isolating them. The result testified that the described method could be widely applied in rapid detection and identification of novel metabolites.
Part 3. Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes
This study is to investigate the kinetic characteristics of a new PPI ilaprazole in Chinese healthy subjects and the association with CYP3A5 and CYP2C19 polymorphisms.21 subjects were selected and treated with 10mg ilaprazole according to their CYP3A5*3 genotypes. The plasma concentrations of ilaprazole and its metabolites were monitored by LC-MS/MS method.The Cmax, AUC(0-6), AUC(0-48) and AUC(0-∞) of ilaprazole were all significantly different across the 3 CYP3A5 genotypes (including 4 of CYP3A5*1/*1,4 of*1/*3,3 of*3/*3; Pb0.05) in CYP2C19 wild-type subjects (CYP2C19 wt/wts), similar variety of Cmax and AUC(0-6) among CYP3A5 genotypes (including 3 of CYP3A5*1/*1,3 of *1/*3,4 of*3/*3; Pb0.05) were also observed in CYP2C19 heterozygous subjects (CYP2C19 wt/mts). The sulfoxidation metabolic index indicates that the CYP3A5*1/*1,*1/*3 (low-expressers), and*3/*3 (no-expressers) groups have medium, lowest and highest activities on ilaprazole metabolism, inconsistent with genotype-based CYP3A5 enzymatic activity. Further analysis showed no correlation between ilaprazole metabolism and CYP2C19 genotypes, evidenced by that the AUC(0-∞) of ilaprazole from either CYP3A5*1/*1 or CYP3A5*1/*3 groups was much higher in CYP2C19 wt/wts (n=4) than that in CYP2C19 wt/mts (n=3) (Pb0.001), but the Cmax and AUC(0-6) of ilaprazole from CYP3A5*3/*3 groups, were significantly lower in CYP2C19 wt/wts (n=3) compared to CYP2C19 wt/mts (n=4) (Pb0.01). There was no demonstrated relationship between ilaprazole metabolism and CYP3A5 polymorphisms.
Part 4. The effect of standard Triple-Drug therapy for helicobacter pylori eradication on the pharmacokinetcs of Ilaprazole
This is a controled, two-period, cross over study. During the first stage all the subjects were orally administrated ilaprazole(5mg) or standard Triple-Drug therapy for helicobacter pylori eradication bid for six continuous days. On the first and seventh day after the morning administation of ilaprazole 5ml of blood samples were drawn from subjects at0,0.5,1,1.5,2,3,4,6,8,12,24,48 and 72 hours, and urine were collected for 24 hours. After one week's wash out period on the second stage of study the subjects were drawn 8 ml of blood sample on the same time points. Plasma concentrations of ilaprazole were determined by a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method, all of the pharmacokinetic parameters were calculated by use of DAS Ver 2.0. The results were ilaprazole of standard Triple-Drug therapy for helicobacter pylori eradication absorbtion rate and absorbtion amount is significantly decreased than single dose of ilaprazole, the absorbtion rate and absorbtion amount of the major metabolite ilaprazole sulfone is significantly decreased than single dose group as well. The absorbtion rate and absorbtion amount of metabolite ilaprazole sulfide is higher the single dose group.
一、液相色谱-串联质谱法测定血浆中艾普拉唑及其代谢产物及在药代动力学上的应用
目的：建立快速、灵敏的液相色谱-串联质谱法测定人血浆中的艾普拉唑及其代谢产物,用于受试者口服艾普拉唑后的药代动力学研究。
方法：选用Thermo HyPURITYC18柱,流动相为10mM甲酸胺水溶液：乙腈(50：50),柱温30度,三重四极杆质谱以多反应监测方式进行检测,检测的离子：艾普拉唑m/z367.2→184.0；艾普拉唑砜：m／z：383.3→184.1；艾普拉唑硫醚：m／z：351.2→168.1；内标奥美拉唑：m／z：346.2→198.0。12名健康受试者分别口服5mg的艾普拉唑肠溶片在0-48h采血,用建立的LC-MS/MS方法检测其体内艾普拉唑及其两个代谢产物的血药浓度。
结果：其线性范围艾普拉唑为0.23-2400.00 ng/mL;艾普拉唑砜为0.05-105.00 ng/mL;艾普拉唑硫醚为0.06-45.00ng/mL。LLOQ分别为0.23、0.05和0.06ng/mL。结论：该方法灵敏度高,实用性强,适用于临床药物动力学研究。
二、人尿中艾普拉唑代谢物的结构鉴定
目的：利用LC-MS/MS和LC-NMR鉴定口服艾普拉唑在人尿中的四种代谢产物
方法：尿样在被Na2CO3溶液(1 mol/L)碱化后,加入适量二氯甲烷以及0.05 mol/L的醋酸铵缓冲溶液进行萃取。选用伊利特C18柱,流动相为甲醇：0.05MNH4AC水溶液,Agilent 1200色谱系统进行检测。
结果：通过HPLC-MS/MS以及HPLC-NMR实验鉴定了健康受试者服用艾普拉唑后尿液中的代谢产物M1-M4。4个代谢产物均为艾普拉唑的醚化产物,艾普拉唑硫醚,12-羟基艾普拉唑硫醚,11,12-二羟基硫醚和艾普拉唑硫醚A。由此,我们推断4个代谢产物的代谢途径为：艾普拉唑首先被代谢酶还原成艾普拉唑硫醚(M1),艾普拉唑硫醚(M1)接着被还原成艾普拉唑硫醚A(M4)以及发生羟基化反应生成12-羟基艾普拉唑硫醚(M2),12-羟基艾普拉唑硫醚(M2)再次发生羟基化反应生成11,12-二羟基艾普拉唑硫醚(M3)。此外,在尿液中未检测到原料药、砜化产物以及去甲基化和羟基化的产物。
三、在中国健康人中研究新型质子泵抑制剂艾普拉唑与CYP3A5和CYP2C19基因型相关的药代动力学
目的：本试验是研究新型质子泵抑制剂艾普拉唑在健康中国受试者中的药代动力学以及和代谢酶CYP3A5和CYP2C19的基因多态性。
方法：在202名健康中国受试者中筛选CYP3A5*3基因型,根据他们的CYP3A5和CYP2C19基因型有21名成年男子入选参加本实验。
在服用单剂量艾普拉唑后利用LC-MS/MS检测艾普拉唑和代谢产物在血浆中的血药浓度。
结果：在CYP2C19野生纯合子及突变杂合子中即所有的受试者中,艾普拉唑和艾普拉唑砜的主要代谢参数在3组CYP3A5基因型中显著变化。虽然CYP3A5高表达(CYP3A5*1／*1)显示比低表达(CYP3A5*1/*3)较高的清除率,但是无表达(CYP3A5*3／*3)在3组不同基因型中有最高的清除率。根据这一结果,可以认为CYP3A5*1／*1、CYP3A5*1/*3、CYP3A5*3／*3,代谢艾普拉唑的能力分别为中、低、高。这一结果提示我们CYP3A5酶活性与艾普拉唑的代谢无关。假如在3组基因型中,CYP3A5基因型-表型与总CYP3A酶活性没有我们预期的相关性,我们就不能用CYP3A5基因型代表总的CYP3A活性。从而得出结论本试验没有发现CYP3A5于艾普拉唑的代谢有相关性。
四、抗幽门螺杆菌三联用药方案对艾普拉唑药物代谢动力学的影响
目的：三联用药方案中多剂量艾普拉唑和非联用方案中多剂量艾普拉唑药代动力学参数差异的研究
方法：本研究为自身前后对照、双周期、双交叉实验。第一阶段连续服用艾普拉唑5 mg Bid×6天。第一天和第七天抽取服药后0,0.5,1,1.5,2,3,4,6,8,12,24,48和72小时的5 ml血样(采用静脉留滞针)和收集服药后0-24小时分段尿。一周洗脱期后开始第二阶段连续服用克拉霉素500 mg Bid+阿莫西林1 g Bid+消旋艾普拉唑5 mg Bid三联用药×6天。抽取相同时间点8 ml血样(采用静脉留滞针)。两组受试者经洗脱期后交换服药方式,采集相应时间点的血药浓度。采用HPLC-MS/MS法测定给药后不同时间艾普拉唑血药浓度,利用DAS Ver2.0计算药动学参数和进行统计分析。
结果：三联用药组艾普拉唑在吸收速度和吸收量上均较单剂量艾普拉唑组降低,代谢产物之一艾普拉唑砜在吸收速度和吸收量上均较单剂量艾普拉唑组降低,而代谢产物艾普拉唑硫醚在吸收速度和吸收量上均较单剂量艾普拉唑组增高。
Ilaprazole is a new proton pump inhibitor designed for the treatment of gastric ulcers. Our study consists of four parts, determination of ilapraozle and its two metabolites in human plasma by LC-MS/MS, Identification of ilaprazole urinary metabolites in human by high-performance liquid chromatography -tandem mass spectrometry and stopped-flow high-performance liquid chromatography-nuclear magnetic resonance experiments, pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes and the effect of standard Triple-Drug therapy for helicobacter pylori eradication on the pharmacokinetcs of Ilaprazole.
Part 1. Determination of ilapraozle and its two metabolites in human plasma by LC-MS/MS
An analytical method based on liquid chromatography and electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) has been improved and validated for the quantitative measurement of ilaprazole and it's two metablites in human plasma. Separation of analytes and the internal standard (IS) omeprazole was performed on a Thermo HyPURITY C18 column (150x2. 1mm,5μm) with a mobile phase consisting of 10mM ammonium formate water solution- acetonitrile (50:50,v/v) at a flow rate of 0.25 mL/min. The API4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring mode via positive electrospray ionization interface using the transition m/z 367.2→m/z184.0 for ilaprazole, m/z 383.3→m/z 184.1 for ilaprazole sulfone, m/z 351.2→m/z168.1 for ilaprazole thiol ether and m/z 346.2→m/z 198.0 for omeprazole. The method was linear over the concentration range of 0.23 - 2400.00 ng/mL for ilaprzole,0.05-105.00 ng/mL for ilaprazole thiol ether and 0.06 - 45.00 ng/mL for ilaprazole sulfone, respectively. The intra- and inter- day prcisions were all less than 15% in terms of relative standard deviation (R.S.D), and the accuracy was within 15% in terms of relative error (R.E) for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.23,0.05 and 0.06 ng/mL with acceptable precision and accuracy for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether, respectively. The validated method offered sensitivity and wide linear concentration range. This method was successfully applied for the evaluation of pharmacokinetics of ilaprazole and it's two metablites after single oral doses of 5 mg ilaprazole to 12 Chinese healthy volunteers.
Part 2. Identification of ilaprazole urinary metabolites in human by high-performance liquid chromatography -tandem mass spectrometry and stopped-flow high-performance liquid chromatography-nuclear magnetic resonance experiments
The structural elucidation of ilaprazole metabolites in human urine was described by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and stopped-flow liquid chromatography-nuclear magnetic resonance (HPLC-NMR) experiments. Urinary samples were precipitated by sodium carbonate solution, and then extracted by liquid-liquid extraction with methyl chloride after adding ammonium acetate buffer. The enriched sample was separated using a C18 reversed-phase column with the mobile phase composed of acetonitrile and 0.05 mol/l ammonium acetate buffer in a gradient solution, and then directly coupled MS/MS detection in an on-line mode or 1H-NMR (500 MHz) spectroscopic detection in a stopped-flow mode. Four sulfide metabolites, ilaprazole sulfide,12-hydroxy-ilaprazole sulfide,11,12-dihydroxy-ilaprazole sulfide and ilaprazole sulfide A were identified from the combined MS/MS and NMR data with those of the parent drug and available standard without actually isolating them. The result testified that the described method could be widely applied in rapid detection and identification of novel metabolites.
Part 3. Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes
This study is to investigate the kinetic characteristics of a new PPI ilaprazole in Chinese healthy subjects and the association with CYP3A5 and CYP2C19 polymorphisms.21 subjects were selected and treated with 10mg ilaprazole according to their CYP3A5*3 genotypes. The plasma concentrations of ilaprazole and its metabolites were monitored by LC-MS/MS method.The Cmax, AUC(0-6), AUC(0-48) and AUC(0-∞) of ilaprazole were all significantly different across the 3 CYP3A5 genotypes (including 4 of CYP3A5*1/*1,4 of*1/*3,3 of*3/*3; Pb0.05) in CYP2C19 wild-type subjects (CYP2C19 wt/wts), similar variety of Cmax and AUC(0-6) among CYP3A5 genotypes (including 3 of CYP3A5*1/*1,3 of *1/*3,4 of*3/*3; Pb0.05) were also observed in CYP2C19 heterozygous subjects (CYP2C19 wt/mts). The sulfoxidation metabolic index indicates that the CYP3A5*1/*1,*1/*3 (low-expressers), and*3/*3 (no-expressers) groups have medium, lowest and highest activities on ilaprazole metabolism, inconsistent with genotype-based CYP3A5 enzymatic activity. Further analysis showed no correlation between ilaprazole metabolism and CYP2C19 genotypes, evidenced by that the AUC(0-∞) of ilaprazole from either CYP3A5*1/*1 or CYP3A5*1/*3 groups was much higher in CYP2C19 wt/wts (n=4) than that in CYP2C19 wt/mts (n=3) (Pb0.001), but the Cmax and AUC(0-6) of ilaprazole from CYP3A5*3/*3 groups, were significantly lower in CYP2C19 wt/wts (n=3) compared to CYP2C19 wt/mts (n=4) (Pb0.01). There was no demonstrated relationship between ilaprazole metabolism and CYP3A5 polymorphisms.
Part 4. The effect of standard Triple-Drug therapy for helicobacter pylori eradication on the pharmacokinetcs of Ilaprazole
This is a controled, two-period, cross over study. During the first stage all the subjects were orally administrated ilaprazole(5mg) or standard Triple-Drug therapy for helicobacter pylori eradication bid for six continuous days. On the first and seventh day after the morning administation of ilaprazole 5ml of blood samples were drawn from subjects at0,0.5,1,1.5,2,3,4,6,8,12,24,48 and 72 hours, and urine were collected for 24 hours. After one week's wash out period on the second stage of study the subjects were drawn 8 ml of blood sample on the same time points. Plasma concentrations of ilaprazole were determined by a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method, all of the pharmacokinetic parameters were calculated by use of DAS Ver 2.0. The results were ilaprazole of standard Triple-Drug therapy for helicobacter pylori eradication absorbtion rate and absorbtion amount is significantly decreased than single dose of ilaprazole, the absorbtion rate and absorbtion amount of the major metabolite ilaprazole sulfone is significantly decreased than single dose group as well. The absorbtion rate and absorbtion amount of metabolite ilaprazole sulfide is higher the single dose group.
引文
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