SLCO1B1基因多态性对瑞格列奈药动学的影响以及PPAR-γ2和PTPRD基因多态性对吡格列酮疗效的影响
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摘要
药物基因组学(pharmacogenomics)是研究个体遗传差异与药物效应之间相互关系的学科。主要研究编码整个基因组范围内所有编码与药物代谢、药物转运、效应相关蛋白质的基因,其主要分子基础是基因多态性(single nucleotide polymorphism, SNP)。
瑞格列奈是一种非磺酰脲类促胰岛素分泌剂,广泛应用于2型糖尿病的治疗。人体试验提示瑞格列奈药动学存在显著的个体差异。我们认为除了人口统计学、个体病理生理不同所致的差异外,其中遗传差异主要源自负责其转运的转运体OATP1B1和MDR1以及负责其代谢的代谢酶CYP3A4, CYP2C8和UGT1A1的基因突变。
为了综合评价这些影响因素对瑞格列奈药动学的影响,我们拟采用群体药动学(Population pharmacokinetics, PPK)分析方法。PPK是将经典的药代动力学原理与统计学模型结合分析,研究药物在某一特定群体中的动力学特征,最终建立数学模型来定量评价各因素对药物药动学的影响。
我们整合了4项瑞格列奈的Ⅰ期临床试验数据,采用群体药动学方法综合评价了SLCO1B1c.521T>C和c.388A>G, CYP3A4*1G, MDR1G2677T/A和C3435T, UGT1A1*6和半28对瑞格列奈药动学的影响。获得SLCO1B1多态影响了瑞格列奈药动学的结果后,在稳转OATP1B1的HEK293细胞系上开展瑞格列奈摄取抑制试验,并选出厄贝沙坦和罗红霉素两个OATP1B1的抑制剂,进行与瑞格列奈的药物相互作用研究。
吡格列酮是一种新型胰岛素增敏药物,属于噻唑烷二酮(TZD)类药物,临床上广泛用于治疗2型糖尿病。有研究报道,吡格列酮治疗2型糖尿病患者的疗效具有显著个体差异。过氧化物酶体增殖物激活受体-y2(PPAR-y2)基因是吡格列酮的靶基因。蛋白酪氨酸磷酸酶受体D (PTPRD) rs17584499是一个由中国汉族人群的GWAS研究筛选出的与2型糖尿病强相关的新基因位点。为此我们研究PPAR-y2rs1801282和PTPRD rs17584499位点与糖尿病的易感性以及对吡格列酮疗效的影响。
我们的研究的主要结果如下：
1.建立了瑞格列奈在中国健康人群的PPK模型,模型显示SLCO1B1c.521T>C突变显著影响了CL/F和V2/F.模型引入SLCO1B1c.521T>C突变后,CL/F和V2/F的个体间差异分别下降3.7%和6.5%。
2.在稳定转染OATP1B1的HEK293细胞系平台上开展的抑制试验显示：厄贝沙坦能显著抑制OATP1B1对[3H]雌酮-3-硫酸盐的转运(IC50=4.65μM)。
3.合用罗红霉素后,瑞格列奈的AUCo-8下降24.5%,但血糖参数改变无统计学意义；合用厄贝沙坦后,TT型个体瑞格列奈的Cmax和AUCo-8显著升高,相应血糖参数也出现明显改变；但TC型个体药动学参数改变无统计学意义,可见SLCO1B1c.521T>C基因型显著影响了药物相互作用的程度；初步判定罗红霉素是OATP1B1的底物,需扩大样本进一步研究。
4.证实了PPAR-γ2rs1801282和PTPRD rs17584499多态性与2型糖尿病易感性显著相关；对于PPAR-γ2rs1801282基因位点,携带CG基因型患者服用吡格列酮后降低FPG和TG效应优于CC基因型患者；对于PTPRD rs17584499基因位点,携带CC基因型患者服用吡格列酮后降低PPG的效应优于CT+TT基因型患者。
本课题从分子、细胞到临床整体水平以及从遗传药理学的角度并借助数学模型探讨了SLCO1B1基因多态对降糖药瑞格列奈药动学的影响和PPAR-y2、PTPRD基因多态对降糖药吡格列酮疗效的影响。本论文旨在为瑞格列奈和吡格列酮在临床上合理使用以及最终实现个体化药物治疗提供科学的理论基础。
Pharmacogenomics is the branch of pharmacology which studies the relationship between individual genetic variation and drug efficacy or toxicity, focusing on all genes coding drug metabolic enzymes, transporters and target proteins within the entire genome. The molecular basis of pharmacogenetics and pharmacogenomics is single nucleotide polymorphism.
Repaglinide is a non-sulfonylurea insulinotropic agent, which has been widely used in the treatment of type2diabetes. Clinal trials suggested that pharmacokinetics of repaglinide had significant individual differences. We proposed that besides demographic and pathophysiological differences, genetic difference was mainly due to the gene mutation of its transporter OATP1B1and MDR1and its metabolic enzymes CYP3A4, CYP2C8and UGT1A1.
In order to comprehensively evaluate the impact of these factors on repaglinide pharmacokinetics, population pharmacokinetics (PPK) analysis was applied. PPK combines classic pharmacokinetic principles with statistical models, studies the dynamic characteristics of drugs in a particular group, and eventually establishes a mathematical model to quantitatively evaluate the impact of various factors on drug pharmacokinetics.
We pooled4separate repaglinide Phase I clinical trial data, and investigated the influence of genetic polymorphisms of SLCO1B1c.521T>C and c.388A>G, CYP3A4*1G, MDR1G2677T/A and C3435T, UGT1A1*6and*28on the pharmacokinetics of repaglinide using population pharmacokinetics quantitative evaluation. It was found that SLCO1B1polymorphism affected the pharmacokinetics of repaglinide. Therefore we performed repaglinide uptake inhibition test in OATP1B1stable transfected HEK293cells, selected irbesartan and roxithromycin as two OATP1B1inhibitors, and furthermore carried out repaglinide drug interaction studies.
Pioglitazone is a novel thiazolidinedione (TZD) insulin-sensitizing drug, which has been widely used in the treatment of type2diabetes. It was reported that the efficacy of pioglitazone in the treatment of type2diabetic patients had significant individual differences. Peroxisome proliferator-activated receptor-y2(PPAR-y2) gene is a target gene of pioglitazone. A Chinese Han population GWAS study identified that protein tyrosine phosphatase receptor D (PTPRD) rs17584499is strongly correlated with type2diabetes. Therefore, we studied the effects of PPAR-y2rs1801282and PTPRD rs17584499on susceptibility of diabetes and pioglitazone efficacy.
The main results of our study are as follows:
1. A repaglinide PPK model of healthy Chinese people was established, showing SLCO1B1c.521T>C mutation significantly affected CL/F and V2/F. When including SLCO1B1c.521T>C mutation in the model, individual difference of CL/F and V2/F decreased by3.7%and6.5%respectively.
2. Inhibition test was carried out in OATP1B1stable transfected HEK293cells line. It was found that irbesartan significantly inhibited [3H]E3S transporter with IC50=4.65μM.
3. Coadministration of roxithromycin significantly decreased repaglinide AUC0-8by24.5%. Coadministration of roxithromycin had no significant effects on glycemic parameters. Irbesartan significantly increased Cmax and AUC0-8of repaglinide in TT genotype subjects, corresponding well with glycemic parameters; while pharmacokinetic parameters in TC genotype subjects were not affected, suggesting that SLCO1B1c.521T> C genotype significantly affect the-extent of drug interactions; roxithromycin might be a substrate of OATP1B1, which needs further larger sample study.
4. PPAR-γ2rs1801282and PTPRD rs17584499polymorphism were associated with susceptibility of type2diabetes. After pioglitazone treatment, type2diabetes patients with PPAR-y2rs1801282CG genotypes showed greater reduction of PPG and TG compared with those with rs1801282CC genotype. The Patients with PTPRD rsl7584499CC genotype had better response to pioglitazone compared to CT+TT genotypes in regards of reducing PPG.
The study explored the effects of SLCO1B1gene polymorphism on the pharmacokinetics of antidiabetic drug repaglinide, and the effects of PPAR-y and PTPRD gene polymorphism on pioglitazone efficacy from molecular, cellular, clinical levels and from the perspective of genetic pharmacology with mathematical models. The aims of this paper are to provide a scientific theoretical foundation for the clinical rational use and the eventual individualized drug therapy of repaglinide and pioglitazone.
瑞格列奈是一种非磺酰脲类促胰岛素分泌剂,广泛应用于2型糖尿病的治疗。人体试验提示瑞格列奈药动学存在显著的个体差异。我们认为除了人口统计学、个体病理生理不同所致的差异外,其中遗传差异主要源自负责其转运的转运体OATP1B1和MDR1以及负责其代谢的代谢酶CYP3A4, CYP2C8和UGT1A1的基因突变。
为了综合评价这些影响因素对瑞格列奈药动学的影响,我们拟采用群体药动学(Population pharmacokinetics, PPK)分析方法。PPK是将经典的药代动力学原理与统计学模型结合分析,研究药物在某一特定群体中的动力学特征,最终建立数学模型来定量评价各因素对药物药动学的影响。
我们整合了4项瑞格列奈的Ⅰ期临床试验数据,采用群体药动学方法综合评价了SLCO1B1c.521T>C和c.388A>G, CYP3A4*1G, MDR1G2677T/A和C3435T, UGT1A1*6和半28对瑞格列奈药动学的影响。获得SLCO1B1多态影响了瑞格列奈药动学的结果后,在稳转OATP1B1的HEK293细胞系上开展瑞格列奈摄取抑制试验,并选出厄贝沙坦和罗红霉素两个OATP1B1的抑制剂,进行与瑞格列奈的药物相互作用研究。
吡格列酮是一种新型胰岛素增敏药物,属于噻唑烷二酮(TZD)类药物,临床上广泛用于治疗2型糖尿病。有研究报道,吡格列酮治疗2型糖尿病患者的疗效具有显著个体差异。过氧化物酶体增殖物激活受体-y2(PPAR-y2)基因是吡格列酮的靶基因。蛋白酪氨酸磷酸酶受体D (PTPRD) rs17584499是一个由中国汉族人群的GWAS研究筛选出的与2型糖尿病强相关的新基因位点。为此我们研究PPAR-y2rs1801282和PTPRD rs17584499位点与糖尿病的易感性以及对吡格列酮疗效的影响。
我们的研究的主要结果如下：
1.建立了瑞格列奈在中国健康人群的PPK模型,模型显示SLCO1B1c.521T>C突变显著影响了CL/F和V2/F.模型引入SLCO1B1c.521T>C突变后,CL/F和V2/F的个体间差异分别下降3.7%和6.5%。
2.在稳定转染OATP1B1的HEK293细胞系平台上开展的抑制试验显示：厄贝沙坦能显著抑制OATP1B1对[3H]雌酮-3-硫酸盐的转运(IC50=4.65μM)。
3.合用罗红霉素后,瑞格列奈的AUCo-8下降24.5%,但血糖参数改变无统计学意义；合用厄贝沙坦后,TT型个体瑞格列奈的Cmax和AUCo-8显著升高,相应血糖参数也出现明显改变；但TC型个体药动学参数改变无统计学意义,可见SLCO1B1c.521T>C基因型显著影响了药物相互作用的程度；初步判定罗红霉素是OATP1B1的底物,需扩大样本进一步研究。
4.证实了PPAR-γ2rs1801282和PTPRD rs17584499多态性与2型糖尿病易感性显著相关；对于PPAR-γ2rs1801282基因位点,携带CG基因型患者服用吡格列酮后降低FPG和TG效应优于CC基因型患者；对于PTPRD rs17584499基因位点,携带CC基因型患者服用吡格列酮后降低PPG的效应优于CT+TT基因型患者。
本课题从分子、细胞到临床整体水平以及从遗传药理学的角度并借助数学模型探讨了SLCO1B1基因多态对降糖药瑞格列奈药动学的影响和PPAR-y2、PTPRD基因多态对降糖药吡格列酮疗效的影响。本论文旨在为瑞格列奈和吡格列酮在临床上合理使用以及最终实现个体化药物治疗提供科学的理论基础。
Pharmacogenomics is the branch of pharmacology which studies the relationship between individual genetic variation and drug efficacy or toxicity, focusing on all genes coding drug metabolic enzymes, transporters and target proteins within the entire genome. The molecular basis of pharmacogenetics and pharmacogenomics is single nucleotide polymorphism.
Repaglinide is a non-sulfonylurea insulinotropic agent, which has been widely used in the treatment of type2diabetes. Clinal trials suggested that pharmacokinetics of repaglinide had significant individual differences. We proposed that besides demographic and pathophysiological differences, genetic difference was mainly due to the gene mutation of its transporter OATP1B1and MDR1and its metabolic enzymes CYP3A4, CYP2C8and UGT1A1.
In order to comprehensively evaluate the impact of these factors on repaglinide pharmacokinetics, population pharmacokinetics (PPK) analysis was applied. PPK combines classic pharmacokinetic principles with statistical models, studies the dynamic characteristics of drugs in a particular group, and eventually establishes a mathematical model to quantitatively evaluate the impact of various factors on drug pharmacokinetics.
We pooled4separate repaglinide Phase I clinical trial data, and investigated the influence of genetic polymorphisms of SLCO1B1c.521T>C and c.388A>G, CYP3A4*1G, MDR1G2677T/A and C3435T, UGT1A1*6and*28on the pharmacokinetics of repaglinide using population pharmacokinetics quantitative evaluation. It was found that SLCO1B1polymorphism affected the pharmacokinetics of repaglinide. Therefore we performed repaglinide uptake inhibition test in OATP1B1stable transfected HEK293cells, selected irbesartan and roxithromycin as two OATP1B1inhibitors, and furthermore carried out repaglinide drug interaction studies.
Pioglitazone is a novel thiazolidinedione (TZD) insulin-sensitizing drug, which has been widely used in the treatment of type2diabetes. It was reported that the efficacy of pioglitazone in the treatment of type2diabetic patients had significant individual differences. Peroxisome proliferator-activated receptor-y2(PPAR-y2) gene is a target gene of pioglitazone. A Chinese Han population GWAS study identified that protein tyrosine phosphatase receptor D (PTPRD) rs17584499is strongly correlated with type2diabetes. Therefore, we studied the effects of PPAR-y2rs1801282and PTPRD rs17584499on susceptibility of diabetes and pioglitazone efficacy.
The main results of our study are as follows:
1. A repaglinide PPK model of healthy Chinese people was established, showing SLCO1B1c.521T>C mutation significantly affected CL/F and V2/F. When including SLCO1B1c.521T>C mutation in the model, individual difference of CL/F and V2/F decreased by3.7%and6.5%respectively.
2. Inhibition test was carried out in OATP1B1stable transfected HEK293cells line. It was found that irbesartan significantly inhibited [3H]E3S transporter with IC50=4.65μM.
3. Coadministration of roxithromycin significantly decreased repaglinide AUC0-8by24.5%. Coadministration of roxithromycin had no significant effects on glycemic parameters. Irbesartan significantly increased Cmax and AUC0-8of repaglinide in TT genotype subjects, corresponding well with glycemic parameters; while pharmacokinetic parameters in TC genotype subjects were not affected, suggesting that SLCO1B1c.521T> C genotype significantly affect the-extent of drug interactions; roxithromycin might be a substrate of OATP1B1, which needs further larger sample study.
4. PPAR-γ2rs1801282and PTPRD rs17584499polymorphism were associated with susceptibility of type2diabetes. After pioglitazone treatment, type2diabetes patients with PPAR-y2rs1801282CG genotypes showed greater reduction of PPG and TG compared with those with rs1801282CC genotype. The Patients with PTPRD rsl7584499CC genotype had better response to pioglitazone compared to CT+TT genotypes in regards of reducing PPG.
The study explored the effects of SLCO1B1gene polymorphism on the pharmacokinetics of antidiabetic drug repaglinide, and the effects of PPAR-y and PTPRD gene polymorphism on pioglitazone efficacy from molecular, cellular, clinical levels and from the perspective of genetic pharmacology with mathematical models. The aims of this paper are to provide a scientific theoretical foundation for the clinical rational use and the eventual individualized drug therapy of repaglinide and pioglitazone.
引文
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