卡马西平的群体药代动力学及其代谢酶CYP3A4基因多态性研究
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摘要
卡马西平(酰胺咪嗪,carbamazepine,CBZ)是目前临床上常用的抗癫痫药物,是治疗癫痫全身性强直--阵挛发作和部分性发作的首选药物之一,可有效控制多种类型的癫痫发作。但由于其有效血药浓度范围(4--12 mg·L-1)较窄、机体对该药物的反应个体差异大以及不良反应较严重等特点,目前临床上通过监测其谷值血药浓度作为调整用药的依据。但不能在用药前预测机体对药物的反应,对确定药物的初始剂量及长期维持剂量没有帮助。目前针对临床个体化给药,主要有两方面的研究。一是群体药代动力学(Population Pharmacokinetics, PPK)研究,此研究可定量地考察患者群体中对药物代谢有影响的因素,全面的反映治疗药物在不同患者个体过程的差异,获得理想的个体药物代谢动力学参数。为临床个体化给药提供更加可靠的依据。二是药物基因组学研究,此研究通过筛选出影响药物代谢的候选基因,研究这些基因多态性与临床表型(如谷值血药浓度,疗效等)的关系,通过筛查患者基因型从更深层次指导临床个体化用药。
本研究回顾性收集了2007年9月～2008年9月在山医大二院临床药学实验室监测卡马西平血药浓度患者的监测结果189例,初步分析了患者年龄、性别、合并用药等因素与血药浓度之间以及血药浓度与临床疗效之间的关系。同时收集2008年10月～2009年9月在山医大二院服用卡马西平癫痫患者的监测结果,以及详细记录患者的一般生物学资料,包括年龄、性别、体重、每日服药剂量、服药时间、合并用药等。利用非线性混合效应模型(nonlinear mixed effect model, NONMEM),建立卡马西平群体药代动力学模型定量考察一般生物学特征对卡马西平代谢的影响。在此期间还收集了141例服用卡马西平癫痫患者的全血标本,筛查卡马西平代谢酶CYP3A4的基因多态性,考察CYP3A4基因多态性对卡马西平代谢的影响。为临床上调整和优化CBZ个体用药方案提供更加全面、可靠的依据。
1、189例癫痫患者卡马西平血药浓度监测结果分析
资料来源：回顾性收集2007年9月18日～2008年9月17日在山医大二院临床药学实验室监测卡马西平血药浓度癫痫患者的监测结果以及患者详细资料。
方法：采用荧光偏振免疫法(fluorescence polarization immunoassay,FPIA)测定卡马西平血药浓度。FPIA法检测原理：根据竞争结合法的原理,标本中抗原与一定量的荧光标记抗原与抗体进行竞争反应,样本中的抗原越多,与抗体结合的标记抗原就越少,从而测得的荧光偏振光度也就越少,所测得的血药浓度相应也就越大。用SPSS11.0软件进行单用卡马西平组与联合用药组有效率之间的比较。疗效评价标准分为完全控制(用药后没有再次发作),有效(发作减少50%--99%)和无效(发作减少<50%)。
结果：(1)1岁以下,1—3岁,4—12岁,13—18岁组卡马西平血药浓度达到治疗窗(4～12 mg·L-1)的百分率分别为0,50.0%,81.3%,93.2%。年龄越大,达到治疗窗的百分率越高。
(2)血药浓度小于4 mg·L-132例,总有效率(完全控制+有效)为62.5%；在4～12mg·L-1有155例,总有效率为73.5%；大于12 mg·L-1有2例,总有效率100%。血药浓度达到治疗窗患者的有效率高于血药浓度低于治疗窗的患者。
(3)卡马西平与癫痫宁等中成药合用时,卡马西平血药浓度达到治疗窗的百分率为79.3%；与托砒酯合用时,血浓达到治疗窗的百分率为87.8%；与丙戊酸合用时,血浓达到治疗窗的百分率为90.9%。
(4)用SPSS11.0软件进行卡方检验,单用卡马西平治疗组与卡马西平联合治疗组进行有效率比较,P值均大于0.05。各组间的差异无统计学意义,尚不能认为单用卡马西平组与联合用药组的总体有效率有差别。
2、卡马西平在癫痫患者中的群体药代动力学研究
资料来源：收集2008年10月～2009年9月在山西医科大学第二医院监测卡马西平血药浓度的癫痫患者的监测结果以及患者一般生物学资料,包括年龄、性别、体重、每日服药剂量、服药时间、合并用药以及不良反应。共收集270例癫痫患者的316个卡马西平血药浓度数据点。
方法：血药浓度测定方法与第一部分相同。采用非线性混合效应模型建立癫痫患者卡马西平的PPK模型,考察患者一般生物学特征对卡马西平药动学参数的影响。应用Bootstrap法对所得PPK模型进行验证。
结果：(1)年龄(AGE)、每日服药剂量(DKG)、体重(BW)均为卡马西平清除率(CL)的影响因素。
(2)所建立的最终模型为：当年龄小于等于14岁时,CL(L/h)=[2.55+0.013×(AGE-15)]×(DKG/.011)0.443×(BW／40)0.392；年龄大于14岁时,CL(L/h)=2.55×(DKG/.011)0.443×(BW/40)0.392。Vd=85L。Vd为表观分布容积。
(3)经Bootstrap法验证,所建模型稳定、可靠。
3、药物代谢酶CYP3A4在服用卡马西平癫痫患者中的遗传多态性
标本来源：收集2008年10月～2009年9月在山西医科大学第二医院临床药学实验室监测卡马西平血药浓度癫痫患者的全血标本。总共收集141例样本,性别、身高、体重不限,均为汉族,无其他合并症且肝肾功能正常的癫痫患者。其中男87例,女54例。年龄1—46岁。
方法：参照OMEGA公司的SE Blood DNA Kit试剂盒说明书从患者全血标本中提取基因组DNA。用聚合酶链反应--限制性片段长度多态性(PCR--RFLP)法对CYP3A4基因进行分型。
结果：在所收集的141例全血标本中,筛查出1例CYP3A4*4突变和1例CYP3A4*6的突变。CYP3A4*4、CYP3A4*5和CYP3A4*6在本研究中的个体突变率分别为1/141、0和1/141。
结论：
(1)不同机体对卡马西平反应的个体差异很大,表现在两个方面：①生理条件相近的病人在接受相同剂量CBZ后,血药浓度测定值差异很大；②血药浓度测定值相同的患者,个体间的临床疗效差异很大。提示临床血药浓度监测只能作为调整用药的依据。
(2)本研究所建立的卡马西平群体药动学模型稳定性好,结合患者的年龄、每日服药剂量、体重可估算出癫痫患者卡马西平的相对清除率,为临床医师制定初始剂量及维持剂量有很大帮助。
(3)在我的研究中还不能得出CYP3A4基因突变与卡马西平代谢之间有关系的结论。
(4)所筛查出的CYP3A4基因突变例数太少,没能将基因多态性因素引入到PPK模型中进行定量研究。需扩大标本进一步研究。
Carbamazepine(CBZ), as one of the most important anti-epileptic agent, is widely used in preventing general rigidity—clonic seizure and partial seizure. Because of the narrow therapeutic window (4--12 mg·L-1), the large individual variation of different patients response to CBZ and the serious adverse reaction, doctors adjust the dosage of CBZ by monitoring its trough serum concentration. But monitoring the trough serum concentration can't predict patients' response to CBZ before taking. It is helpless to determine the initial dose and long-term maintain dose. Now, there are two kind of studies on determining rational individual regimen for drugs. One is population pharmacokinetics (PPK) study. The PPK study can investigate the factors that affect drug metabolism, illustrate the variability of pharmacokinetic of therapeutic drugs in a diverse population and obtain ideal individual PK parameters. The second study is pharmacogenomics. The candidate genes that affects drug metabolism are selected out by pharmacogenomics.Then we can investigate the relations between genetic polymorphism and clinical phenotype (such as trough serum concentration, curative effect et al). It provides a more reliable basis for individual therapy by learning the genotype of different patients.
We collected the monitoring results of CBZ serum concentrations retrospectively from September 2007 to September 2008.The CBZ serum concentrations were determined in Shanxi Medical University the Second Hospital clinical pharmacy laboratory. The study analyzes the relations between age, gender, treated with other drugs and serum concentrations, and between serum concentrations and curative effect. We also collected the monitoring results of CBZ serum concentrations and the general demographic information of the patients, including age、gender、weight、dosage、time and co-administration from October 2008 to September 2009. The population phamacokinetics model of carbamazepine in patients with epileptic was built using nonlinear mixed effect model. The influence of the general demographic information on PK parameters of CBZ was investigated. We also collected 141 whole blood samples of the epileptic patients treated with CBZ, determined the CYP3A4 genetic polymorphism, investigated the influence of CYP3A4 genetic polymorphism on CBZ metabolism. It provides a more reliable basis for the rational individual regimen for CBZ.
Part one:Monitoring results of blood concentration of carbamazepine in 189 cases with epileptic
Materials:We collected the monitoring results of blood concentration of carbamazepine in patients with epileptic and detailed information associated with these patients from October 2008 to September 2009. All the patients were monitored in the clinical pharmacy laboratory of Shanxi Medical University the Second Hospital.
Methods:The blood concentration of carbamazepine were determined by the method of fluorescence polarization immunassay(FPIA). The principle of FPIA:According to the principle of competition-binding assay, the antigen in the specimens and a certain amount of fluorescent labeled antigen combine with antibody competitively. If the antigen in the specimens is more, the fluorescent labeled antigen combined with antibody is less. Thus the measured fluorescence polarization luminosity is also less. So the measured blood concentration is greater accordingly. Comparing the effective rate between the group of only using CBZ and the group of using CBZ and other antiepileptic drugs by SPSS 11.0. The evaluation criteria are divided into completely control, effective and invalid.
Results:(1) The percentage of the blood concentration of CBZ reached the therapeutic window in the group of 1 year,1-3 years old,4-12 years old and 13-18 years old are 0,50.0%, 81.3% and 93.2% respectively. The percentage of the blood concentration of CBZ reached the therapeutic window is higher along with increasing age.
(2) The blood cencentration of 32 cases was less than 4 mg·L-1,among them 20 cases were effective(62.5%);2cases were more than 12 mg·L-1,2cases were effective(100%);the concentration of 155 cases was 4--12 mg·L-1, among them 114 cases were effective(73.5%). The effective rate of CBZ blood concentration reached the therapeutic window is higher than under the therapeutic window.
(3) The percentage of CBZ blood concentration reached the therapeutic window is 79.3% when the epileptic patients received CBZ and Chinese traditional medicine; The percentage is 87.8% when the epileptic patients received CBZ and TMP; The percentage is 90.9% when the epileptic patients received CBZ and VPA.
(4) The chi square test results of comparing the effective rate between the group of only using CBZ and the group of using CBZ and other antiepileptic drugs show no statistically significant(P>0.05). We don't think the effective rate of the two groups is different.
Part two:Population phamacokinetics of carbamazepine in patients with epileptic
Materials:We collected the monitoring results of blood concentration of carbamazepine from October 2008 to September 2009. All the patients were monitored in the clinical pharmacy laboratory of Shanxi Medical University the Second Hospital. We also collected the general demographic information of the patients with epileptic, including age、gender、weight、dosage、time and adverse reaction. We got 316 CBZ blood concentrations of 270 patients with epileptic. Method:The blood concentrations of carbamazepine were determined using the method of part one. The population phamacokinetics model of carbamazepine in patients with epileptic was built using nonlinear mixed effect model. The influence of the general demographic information on PK parameters of CBZ was investigated. Bootstrap was applied to validate the PPK model.
Results:(1) Age、dose and weight are the factors that affect the clearance of CBZ.
(2)The final models of CBZ were:CL (L/h)=[2.55+0.013×(AGE-15)]×(DKG/.011)0.443×(BW/40)0.392 as age<=14; when age>14, CL (L/h)=2.55×(DKG/.011)0.443×(BW/40)0.392。Vd=85L。
(3) The model was stable and reliable by bootstrap.
Part three:Genetic polymorphism of CYP3A4 in epileptic patients treated with CBZ
Materials:We collected the whole blood samples of the epileptic patients treated with CBZ from October 2008 to September 2009. All the patients were monitored in the clinical pharmacy laboratory of Shanxi Medical University the Second Hospital. A total of 141 samples were collected. Gender height and weight of the epileptic patients were not limited. All the epileptic patients are Han people, normal hepatic and renal function, without other complications.87cases were male and 54 cases were female. The span of age is 1—46.
Method:Genemic DNA was extracted from whole blood samples according to the directions of SE blood DNA kit(OMEGA). CYP3A4 genotype was determined by polymerase chain reaction—restriction fragment length polymorphism.
Results:In 141 whole blood samples, we find out 1 CYP3A4*4 mutation and 1 CYP3A4*6 mutation. The gene frequencys of CYP3A4*4、*5 and *6 were 1/141、0 and 1/141,respectively.
Conclusions:
(1) The individual variation of different patients response to CBZ is tremendous. Manifested in two aspects:①Although patients with similar physiological conditions received the same dose of CBZ, the variation of the blood concentrations is large.②The blood concentrations of the epileptic patients is same, but the variation of curative effect is large. Monitoring the blood concentration is only the basis of adjusting the dosage of CBZ.
(2) The PPK model of CBZ showed good stability and it can be used to estimate the relative clearance of CBZ. It is very helpful to determine the initial dose and maintain dose for doctors.
(3) The conclusion that CYP3A4 genetic mutation could influence CBZ metabolism is still not sure in my study.
(4) We only find out two cases of CYP3A4 genetic mutation, so we can't introduce the factor of genetic polymorphism into the PPK model. We need to enlarge the samples for the further study.
本研究回顾性收集了2007年9月～2008年9月在山医大二院临床药学实验室监测卡马西平血药浓度患者的监测结果189例,初步分析了患者年龄、性别、合并用药等因素与血药浓度之间以及血药浓度与临床疗效之间的关系。同时收集2008年10月～2009年9月在山医大二院服用卡马西平癫痫患者的监测结果,以及详细记录患者的一般生物学资料,包括年龄、性别、体重、每日服药剂量、服药时间、合并用药等。利用非线性混合效应模型(nonlinear mixed effect model, NONMEM),建立卡马西平群体药代动力学模型定量考察一般生物学特征对卡马西平代谢的影响。在此期间还收集了141例服用卡马西平癫痫患者的全血标本,筛查卡马西平代谢酶CYP3A4的基因多态性,考察CYP3A4基因多态性对卡马西平代谢的影响。为临床上调整和优化CBZ个体用药方案提供更加全面、可靠的依据。
1、189例癫痫患者卡马西平血药浓度监测结果分析
资料来源：回顾性收集2007年9月18日～2008年9月17日在山医大二院临床药学实验室监测卡马西平血药浓度癫痫患者的监测结果以及患者详细资料。
方法：采用荧光偏振免疫法(fluorescence polarization immunoassay,FPIA)测定卡马西平血药浓度。FPIA法检测原理：根据竞争结合法的原理,标本中抗原与一定量的荧光标记抗原与抗体进行竞争反应,样本中的抗原越多,与抗体结合的标记抗原就越少,从而测得的荧光偏振光度也就越少,所测得的血药浓度相应也就越大。用SPSS11.0软件进行单用卡马西平组与联合用药组有效率之间的比较。疗效评价标准分为完全控制(用药后没有再次发作),有效(发作减少50%--99%)和无效(发作减少<50%)。
结果：(1)1岁以下,1—3岁,4—12岁,13—18岁组卡马西平血药浓度达到治疗窗(4～12 mg·L-1)的百分率分别为0,50.0%,81.3%,93.2%。年龄越大,达到治疗窗的百分率越高。
(2)血药浓度小于4 mg·L-132例,总有效率(完全控制+有效)为62.5%；在4～12mg·L-1有155例,总有效率为73.5%；大于12 mg·L-1有2例,总有效率100%。血药浓度达到治疗窗患者的有效率高于血药浓度低于治疗窗的患者。
(3)卡马西平与癫痫宁等中成药合用时,卡马西平血药浓度达到治疗窗的百分率为79.3%；与托砒酯合用时,血浓达到治疗窗的百分率为87.8%；与丙戊酸合用时,血浓达到治疗窗的百分率为90.9%。
(4)用SPSS11.0软件进行卡方检验,单用卡马西平治疗组与卡马西平联合治疗组进行有效率比较,P值均大于0.05。各组间的差异无统计学意义,尚不能认为单用卡马西平组与联合用药组的总体有效率有差别。
2、卡马西平在癫痫患者中的群体药代动力学研究
资料来源：收集2008年10月～2009年9月在山西医科大学第二医院监测卡马西平血药浓度的癫痫患者的监测结果以及患者一般生物学资料,包括年龄、性别、体重、每日服药剂量、服药时间、合并用药以及不良反应。共收集270例癫痫患者的316个卡马西平血药浓度数据点。
方法：血药浓度测定方法与第一部分相同。采用非线性混合效应模型建立癫痫患者卡马西平的PPK模型,考察患者一般生物学特征对卡马西平药动学参数的影响。应用Bootstrap法对所得PPK模型进行验证。
结果：(1)年龄(AGE)、每日服药剂量(DKG)、体重(BW)均为卡马西平清除率(CL)的影响因素。
(2)所建立的最终模型为：当年龄小于等于14岁时,CL(L/h)=[2.55+0.013×(AGE-15)]×(DKG/.011)0.443×(BW／40)0.392；年龄大于14岁时,CL(L/h)=2.55×(DKG/.011)0.443×(BW/40)0.392。Vd=85L。Vd为表观分布容积。
(3)经Bootstrap法验证,所建模型稳定、可靠。
3、药物代谢酶CYP3A4在服用卡马西平癫痫患者中的遗传多态性
标本来源：收集2008年10月～2009年9月在山西医科大学第二医院临床药学实验室监测卡马西平血药浓度癫痫患者的全血标本。总共收集141例样本,性别、身高、体重不限,均为汉族,无其他合并症且肝肾功能正常的癫痫患者。其中男87例,女54例。年龄1—46岁。
方法：参照OMEGA公司的SE Blood DNA Kit试剂盒说明书从患者全血标本中提取基因组DNA。用聚合酶链反应--限制性片段长度多态性(PCR--RFLP)法对CYP3A4基因进行分型。
结果：在所收集的141例全血标本中,筛查出1例CYP3A4*4突变和1例CYP3A4*6的突变。CYP3A4*4、CYP3A4*5和CYP3A4*6在本研究中的个体突变率分别为1/141、0和1/141。
结论：
(1)不同机体对卡马西平反应的个体差异很大,表现在两个方面：①生理条件相近的病人在接受相同剂量CBZ后,血药浓度测定值差异很大；②血药浓度测定值相同的患者,个体间的临床疗效差异很大。提示临床血药浓度监测只能作为调整用药的依据。
(2)本研究所建立的卡马西平群体药动学模型稳定性好,结合患者的年龄、每日服药剂量、体重可估算出癫痫患者卡马西平的相对清除率,为临床医师制定初始剂量及维持剂量有很大帮助。
(3)在我的研究中还不能得出CYP3A4基因突变与卡马西平代谢之间有关系的结论。
(4)所筛查出的CYP3A4基因突变例数太少,没能将基因多态性因素引入到PPK模型中进行定量研究。需扩大标本进一步研究。
Carbamazepine(CBZ), as one of the most important anti-epileptic agent, is widely used in preventing general rigidity—clonic seizure and partial seizure. Because of the narrow therapeutic window (4--12 mg·L-1), the large individual variation of different patients response to CBZ and the serious adverse reaction, doctors adjust the dosage of CBZ by monitoring its trough serum concentration. But monitoring the trough serum concentration can't predict patients' response to CBZ before taking. It is helpless to determine the initial dose and long-term maintain dose. Now, there are two kind of studies on determining rational individual regimen for drugs. One is population pharmacokinetics (PPK) study. The PPK study can investigate the factors that affect drug metabolism, illustrate the variability of pharmacokinetic of therapeutic drugs in a diverse population and obtain ideal individual PK parameters. The second study is pharmacogenomics. The candidate genes that affects drug metabolism are selected out by pharmacogenomics.Then we can investigate the relations between genetic polymorphism and clinical phenotype (such as trough serum concentration, curative effect et al). It provides a more reliable basis for individual therapy by learning the genotype of different patients.
We collected the monitoring results of CBZ serum concentrations retrospectively from September 2007 to September 2008.The CBZ serum concentrations were determined in Shanxi Medical University the Second Hospital clinical pharmacy laboratory. The study analyzes the relations between age, gender, treated with other drugs and serum concentrations, and between serum concentrations and curative effect. We also collected the monitoring results of CBZ serum concentrations and the general demographic information of the patients, including age、gender、weight、dosage、time and co-administration from October 2008 to September 2009. The population phamacokinetics model of carbamazepine in patients with epileptic was built using nonlinear mixed effect model. The influence of the general demographic information on PK parameters of CBZ was investigated. We also collected 141 whole blood samples of the epileptic patients treated with CBZ, determined the CYP3A4 genetic polymorphism, investigated the influence of CYP3A4 genetic polymorphism on CBZ metabolism. It provides a more reliable basis for the rational individual regimen for CBZ.
Part one:Monitoring results of blood concentration of carbamazepine in 189 cases with epileptic
Materials:We collected the monitoring results of blood concentration of carbamazepine in patients with epileptic and detailed information associated with these patients from October 2008 to September 2009. All the patients were monitored in the clinical pharmacy laboratory of Shanxi Medical University the Second Hospital.
Methods:The blood concentration of carbamazepine were determined by the method of fluorescence polarization immunassay(FPIA). The principle of FPIA:According to the principle of competition-binding assay, the antigen in the specimens and a certain amount of fluorescent labeled antigen combine with antibody competitively. If the antigen in the specimens is more, the fluorescent labeled antigen combined with antibody is less. Thus the measured fluorescence polarization luminosity is also less. So the measured blood concentration is greater accordingly. Comparing the effective rate between the group of only using CBZ and the group of using CBZ and other antiepileptic drugs by SPSS 11.0. The evaluation criteria are divided into completely control, effective and invalid.
Results:(1) The percentage of the blood concentration of CBZ reached the therapeutic window in the group of 1 year,1-3 years old,4-12 years old and 13-18 years old are 0,50.0%, 81.3% and 93.2% respectively. The percentage of the blood concentration of CBZ reached the therapeutic window is higher along with increasing age.
(2) The blood cencentration of 32 cases was less than 4 mg·L-1,among them 20 cases were effective(62.5%);2cases were more than 12 mg·L-1,2cases were effective(100%);the concentration of 155 cases was 4--12 mg·L-1, among them 114 cases were effective(73.5%). The effective rate of CBZ blood concentration reached the therapeutic window is higher than under the therapeutic window.
(3) The percentage of CBZ blood concentration reached the therapeutic window is 79.3% when the epileptic patients received CBZ and Chinese traditional medicine; The percentage is 87.8% when the epileptic patients received CBZ and TMP; The percentage is 90.9% when the epileptic patients received CBZ and VPA.
(4) The chi square test results of comparing the effective rate between the group of only using CBZ and the group of using CBZ and other antiepileptic drugs show no statistically significant(P>0.05). We don't think the effective rate of the two groups is different.
Part two:Population phamacokinetics of carbamazepine in patients with epileptic
Materials:We collected the monitoring results of blood concentration of carbamazepine from October 2008 to September 2009. All the patients were monitored in the clinical pharmacy laboratory of Shanxi Medical University the Second Hospital. We also collected the general demographic information of the patients with epileptic, including age、gender、weight、dosage、time and adverse reaction. We got 316 CBZ blood concentrations of 270 patients with epileptic. Method:The blood concentrations of carbamazepine were determined using the method of part one. The population phamacokinetics model of carbamazepine in patients with epileptic was built using nonlinear mixed effect model. The influence of the general demographic information on PK parameters of CBZ was investigated. Bootstrap was applied to validate the PPK model.
Results:(1) Age、dose and weight are the factors that affect the clearance of CBZ.
(2)The final models of CBZ were:CL (L/h)=[2.55+0.013×(AGE-15)]×(DKG/.011)0.443×(BW/40)0.392 as age<=14; when age>14, CL (L/h)=2.55×(DKG/.011)0.443×(BW/40)0.392。Vd=85L。
(3) The model was stable and reliable by bootstrap.
Part three:Genetic polymorphism of CYP3A4 in epileptic patients treated with CBZ
Materials:We collected the whole blood samples of the epileptic patients treated with CBZ from October 2008 to September 2009. All the patients were monitored in the clinical pharmacy laboratory of Shanxi Medical University the Second Hospital. A total of 141 samples were collected. Gender height and weight of the epileptic patients were not limited. All the epileptic patients are Han people, normal hepatic and renal function, without other complications.87cases were male and 54 cases were female. The span of age is 1—46.
Method:Genemic DNA was extracted from whole blood samples according to the directions of SE blood DNA kit(OMEGA). CYP3A4 genotype was determined by polymerase chain reaction—restriction fragment length polymorphism.
Results:In 141 whole blood samples, we find out 1 CYP3A4*4 mutation and 1 CYP3A4*6 mutation. The gene frequencys of CYP3A4*4、*5 and *6 were 1/141、0 and 1/141,respectively.
Conclusions:
(1) The individual variation of different patients response to CBZ is tremendous. Manifested in two aspects:①Although patients with similar physiological conditions received the same dose of CBZ, the variation of the blood concentrations is large.②The blood concentrations of the epileptic patients is same, but the variation of curative effect is large. Monitoring the blood concentration is only the basis of adjusting the dosage of CBZ.
(2) The PPK model of CBZ showed good stability and it can be used to estimate the relative clearance of CBZ. It is very helpful to determine the initial dose and maintain dose for doctors.
(3) The conclusion that CYP3A4 genetic mutation could influence CBZ metabolism is still not sure in my study.
(4) We only find out two cases of CYP3A4 genetic mutation, so we can't introduce the factor of genetic polymorphism into the PPK model. We need to enlarge the samples for the further study.
引文
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[23]储小曼,闵佩清,张静,等.药物代谢酶CYP3A在中国肾移植人群的遗传多态性.医学研究生学报,2005,18(2)：107-111.
[24]王弘,文思远,郭代红,等.肾移植患者的CYP3A4基因型与体内环孢素浓度相关性评价.中国新药杂志,2005,,14卷(12)：1462-1465.
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[2]芮建中,张震.群体药代动力学／群体药效动力学原理及研究方法.医学研究生学报,2005,18(3)：246-249
[3]王辉.肝移植术后他克莫司谷值血药浓度与供肝CYP3A4基因型及重量关系的研究：[硕士学位论文].天津：天津医科大学,2007
[4]李珍,陈刚.群体药动学研究中非线性混合效应模型法的评价和应用.国外医学药学分册,1993,20(4)：195-199.
[5]廖清船,徐康康.抗癫痫药遗传药理学研究进展.中国医院药学杂志,2007,27(12)：1731-1733.
[6]高玫梅.细胞色素P4503A基因表达调控及与抗癫痫药物的关系.现代临床医学生物工程学杂志,2005,11(5)：381-383.
[7]Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals:studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther,1994,270 (1):412.
[8]彭华,程泽能.细胞色素P450-3A4相关的药物相互作用.Chin J Clin Pharmacol,2001,17(5):379-385.
[9]Hashimoto H, Toide K, Kitamura R, et al. Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem,1993,218:585-595.
[10]王安,周宏濒.细胞色素氧化酶CYP3A4基因突变与表型研究进展.Chin J Clin Pharmacol,2005,21(6):459-462.
[11]Paris PL, Kupelian PA, Hall JM, et al. Association between a CYP3A4 genetic variant and clinical presentation in African-American prostate cancer patients. Cancer Epidemiol Biomarkers Prev,1999,8:901.
[12]Eiselt R, Domanski TL, Zibat A, et al. Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics,2001,11:447.
[13]Dai D, Tang J, Rose R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther,2001,299: 825.
[14]Sata F, Sapone A, Elizondo G, et al. CYP3A4 allelic variants with amino caid substitutions in exons 7 and 12:evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther,2000,67:48.
[15]Hsich KP, Lin YY, Cheng CL, et al. Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos,2001,29:268.
[16]储小曼,阂佩清,张静,等.药物代谢酶CYP3A在中国肾移植人群的遗传多态性.医学研究生学报,2005,18(2)：107-111.
[17]姜德春,白向荣,王育琴,等.抗癫痫药的群体药代动力学与CYP450基因多态性的研究进展.中国临床药理学与治疗学,2006,11(11)：1207-1212.
[18]Mamiya K,Ieiri I,Shimamoto J,et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy:studies in stereo selective hydroxylation and population pharmacokinetics. Epilepsia,1998,39:1317-1323.
[19]Mamiya K,Hadama A, Yukawa E,et al. CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy analysis by population pharmacokinetics. Eur J Cli Pharmacol,2000,55:821-825.
[20]Hung CC.Dosage recommendation of phenytoin for patient with epilepsy with different CYP2C9/CYP2C19 polymorphisms.Ther Drug Monit,2004,26:534-40.
[21]申鼎烈.癫痫治疗的现状.中国神经精神疾病杂志,2001,27(1)：1.
[22]李家泰.临床药理学.北京：人民卫生出版社,1999：207.
[23]卢建,张旭晖.丙戊酸钠与卡马西平合用治疗癫痴患儿的血药质量浓度监测.实用儿科临床杂志,2004,19(10)：879.
[24]陈小杰.妥泰治疗卡马西平治疗疗效不佳的癫痫患儿39例分析.中国全科医学,2005,8(20)：1698.
[25]李金恒.临床治疗药物监测的方法和应用.北京：人民卫生出版社,2003：28.
[26]Sheiner LB, Beal SL, Ro senberg B, et al. Fo recasting individual pharmacokinetics Clin Pharmaco Ther,1979,26:294
[27]焦正,钟明康,施孝金,等.NONMEM法估算中国癫痫患者卡马西平的清除率.中国药理学通报,2003,19(3)：314-318.
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