The Role of P-glycoprotein in Sitagliptin Clinical Pharmacology

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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.