The Role of P-glycoprotein in Sitagliptin Clinical Pharmacology

描述（由申请人提供）： 西格列汀是一种二肽基肽酶-4抑制剂，是治疗2型糖尿病的最新口服药物。作为一种新的口服降糖药，该药的临床药理学存在许多未解之谜。目前，遗传变异影响西格列汀药代动力学个体间变异的程度（即，处置）和药效学（即，答案是未知的。此外，很少进行正式的药物相互作用研究，以检查西格列汀与常规用于治疗糖尿病合并症（如血脂异常）的药物联合给药时的处置。鉴于西格列汀临床药理学知识的这些显著差距，本申请中拟定的研究旨在阐明西格列汀治疗的药物遗传学、药代动力学和药物相互作用。关于药物遗传学和药代动力学，体外数据显示西格列汀是药物外排转运蛋白P-糖蛋白的底物。常见的功能多态性存在于多药耐药1（MDR 1），基因编码的P-糖蛋白，这些多态性往往是在单倍型的形式进行研究。然而，尚未研究多态性MDR 1单倍型对西格列汀人体药代动力学的影响程度。作为一种P-糖蛋白底物，西格列汀也易与伴随给药的P-糖蛋白抑制剂发生药代动力学药物相互作用。阿托伐他汀是一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类），常用于治疗2型糖尿病患者的血脂异常。阿托伐他汀是 P-糖蛋白抑制剂可能会增加血浆暴露量并减少P-糖蛋白底物（例如西格列汀）的肾脏消除。然而，阿托伐他汀改变西格列汀药代动力学的程度尚不清楚。鉴于这些未回答的问题，本申请中提出的主要假设为：假设1：MDR 1多态性导致西格列汀药代动力学的个体间变异性。具体目的1：确定不同MDR 1双倍型的健康受试者之间是否存在西格列汀药代动力学参数差异。假设二：阿托伐他汀和西格列汀之间存在药代动力学药物相互作用，因此阿托伐他汀抑制P-糖蛋白介导的西格列汀转运并增加西格列汀血药浓度。具体目标二：在健康受试者中，比较西格列汀单独给药与西格列汀与阿托伐他汀联合给药时的西格列汀药代动力学参数。本研究的长期目标是提供临床药理学数据，帮助临床医生安全合理地使用口服降糖药物治疗。 公共卫生相关性：2型糖尿病的治疗是具有挑战性的，大多数患者需要多种药物来实现充分的血糖控制。西格列汀是一种新的口服糖尿病药物，关于该药物在患者中的药理学，存在许多未回答的问题（即，临床药理学）。本申请的目的是研究西格列汀的临床药理学，以促进其在2型糖尿病患者中的安全有效使用。

DESCRIPTION (provided by applicant): Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is the newest oral medication available to treat type 2 diabetes. As a new oral antidiabetic agent, numerous unanswered questions exist regarding the clinical pharmacology of this drug. Currently, the extent to which genetic variation influences interindividual variability in sitagliptin pharmacokinetics (i.e., disposition) and pharmacodynamics (i.e., response) is not known. Furthermore, few formal drug-drug interaction studies have been conducted which examine the disposition of sitagliptin when it is administered with medications that are routinely used to treat diabetic co-morbid conditions, such as dyslipidemia. In light of these significant gaps in sitagliptin clinical pharmacology knowledge, the purpose of the study proposed within this application is to elucidate the pharmacogenetics, pharmacokinetics, and drug-drug interactions of sitagliptin therapy. In regard to pharmacogenetics and pharmacokinetics, in vitro data show that sitagliptin is a substrate for P-glycoprotein, a drug efflux transporter. Common functional polymorphisms exist in multidrug resistance 1 (MDR1), the gene that encodes P-glycoprotein, and these polymorphisms are often studied in haplotype form. However, the extent to which polymorphic MDR1 haplotypes influence sitagliptin pharmacokinetics in humans has not been studied. As a P-glycoprotein substrate, sitagliptin is also susceptible to pharmacokinetic drug-drug interactions with concomitantly administered P-glycoprotein inhibitors. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), is routinely used to treat dyslipidemia in patients with type 2 diabetes. Atorvastatin is a P- glycoprotein inhibitor and may increase plasma exposure and decrease renal elimination of P-glycoprotein substrates, such as sitagliptin. However, the extent to which atorvastatin alters sitagliptin pharmacokinetics is not known. Given these unanswered questions, the primary hypotheses proposed within this application are: Hypothesis 1: MDR1 polymorphisms contribute to interindividual variability in the pharmacokinetics of sitagliptin. Specific Aim 1: Determine if differences in sitagliptin pharmacokinetic parameters exist among healthy subjects with different MDR1 diplotypes. Hypothesis 2: A pharmacokinetic drug-drug interaction exists between atorvastatin and sitagliptin, whereby atorvastatin inhibits P-glycoprotein-mediated transport of sitagliptin and increases sitagliptin plasma concentrations. Specific Aim 2: Compare sitagliptin pharmacokinetic parameters when sitagliptin is administered alone versus when sitagliptin is administered with atorvastatin in healthy subjects. The long term objective of this line of research is to provide clinical pharmacology data that will aid clinicians in the safe and rationale use of oral antidiabetic drug therapy. PUBLIC HEALTH RELEVANCE: The treatment of type 2 diabetes is challenging, with most patients requiring multiple medications to achieve adequate blood glucose control. Sitagliptin is a new oral diabetes medication and there are numerous unanswered questions regarding the pharmacology of this drug in patients (i.e., clinical pharmacology). The aims of this application are to investigate the clinical pharmacology of sitagliptin in order to promote its safe and effective use in patients with type 2 diabetes.