CYP2C9and SLCO1B1Polymorphisms On Metabolism And Drug-drug Interaction Of Nateglinide

World Health Organization (WHO) published that the number of patients with diabetes mellitus (DM) is approximately347million worldwide. In2004, an estimated3.4million people died from consequences of high blood glucose. It is projedted that diabetes deaths will increase by two thirds between2008and2030。 A epidemiological investigation of diabetes in Chinese adults20-year of age or older, points out that92.4million adults (9.7%of the adult population) have diabetes,148.2million adults (15.5%) have prediabetes which is an important risk factor for the development of overt diabetes and cardiovascular disease. More than90%of diabetes is type2diabetes. Oral hypoglycemic drugs are needed for type2diabetes patients whose blood glucose could not be controlled by diet adjustment and exercises. Common oral hypoglycemic drugs are biguanides, thiazolidinediones, sulfonylureas, glinides and a-glucosidase inhibitors. Nateglinide is one of the non-sulfonylurea insulinotropic agents, stimulating pancreatic13-cell secretion by acting on ATP-sensitive K+channels and on voltage-sensitive Ca2+channels. Predominantly stimulating early insulin secretion, leaving the late phase of insulin secretion and fasting insulin unaffected, nateglinide mainly reduces postprandial hyperglycaemia and may confer a relatively lower risk of subsequent hypoglycaemia (2.4%). Through pharmacogenetics studies for years, inherited variations in activities of drug-metabolizing enzymes, receptors or transporters are involved in interindividual differences in drug metabolism, disposition, efficacy and drug-drug interaction. Although genetic polymorphisms of hepatic metabolizing enzymes involved in phase I and phase II reactions have been intensively investigated, the role of genetic variations in the transporters that act in the liver and kidney gains increasingly attention. Commonly, both transporters and metabolizing enzymes simultaneously take part in the metabolism of majority of clinical drugs. However, most of the previous pharmacogenetic studies are limited in the polymorphism of one metabolizing drug or transporter. In vitro studies indicated that nateglinide may be taken into hepatocyte by OATP1B1and metabolized by CYP2C9.Organic anion transporting polypeptide (OATP)1B1(also named OATP-C, OATP2, LST-1) encoded by SLCO1B1, predominantly located on the basolateral membrane of human hepatocyte, transporting many endogenous substances and clinical drugs, such as bile acids, statins and irinotecan.521T>C (Va1174Ala) and388A>G (Asn130Asp) are the two major polymorphisms in Asian, the frequencies are10-15%and60-90%respectively.521T>C polymorphism significantly increase the plasma concentration of some OATP1B1substrates, such as simvastatin, atorvastatin, pravastatin, rosuvstatin, repaglinide and nateglinide. Cytochrome P450(CYP) superfamily is the most important phase I metabolizing enzymes. CYP2C9takes part in the metabolism of about20%of clinical drugs, such as warfarin, losartan, glimepiride, glibenclamide and glipizide. CYP2C9*3is the most common mutation in Chinese with the frequency of3.3%. CYP2C9*3could markedly decrease the catalytic activity of CYP2C9enzyme.Both diabetes and tuberculosis are the common diseases. People with diabetes have a significantly increased risk of developing active tuberculosis,2-3times higher. The chance for simultaneous use of antitubercular agent rifampicin and oral hypoglycemic drugs is increasing. Rifampicin is a classic inducer of drug metabolizing enzyme and transporter for clinical research. Multiple-dose rifampicn can elevated the expression of CYP3A4, CYP2C9, P-gp or MRP2protein by stimulating nuclear receptor PXR. Rifampicin is transported by OATP1B1and OATP8, it markedly increases the drug concentration when coadministration with OATP1B1substrate.Based on these information, our study was performed in healthy male Chinese subjects to clarify the effect of CYP2C9and OATP1B1polymorphisms on PK and PD of nateglinide, to investigate the influence of single-dose rifampicin and multiple-dose rifampicin on PK and PD of nateglinide and the role of CYP2C9and OATP1B1polymorphisms on these natglinide and rifampicin drug-drug interaction. The major findings are listed below:1. In accordance with the previous reports, the frequencies of CYP2C9*3, SLCOIBI521T>C and388A>G variant alleles in Chinese population were5.6%,74.3%and13.6%.2. We firstly synthetically studied the effect of CYP2C9*3and SLCO1B1521T>C polymorphisms on PK and PD of nateglinide, and found both of them could increase the plasma concentration of nateglinide. These two genetic polymorphisms only partially explained the interindividual difference of natglinide (approximately30-40%), and CYP2C9*3seemed more powerful. However, no influence was found in the PD of nateglinide. These suggested other genetic polymorphisms may be involved, such as the variants in drug receptor or protein participated in the metabolism of blood glucose.3. According to the frequency and time of nateglinide administration, different results were obtained. Coadministration with nateglinide, single-dose rifampicin significantly increased the plasma concentration of nateglinide and its hypoglycemic effect. Whereas multiple-dose rifampicin markedly decreased the plasma concentration of nateglinide, leaving the hypoglycemic effect unaffected.4. The important role of CYP2C9in the metabolism of nateglinide was confirmed in the study. CYP2C9*3could remarkably weaken the influence of single-dose rifampicin on the PK and PD of nateglinide. CYP2C9*3had no significant relationship with the influence of multiple-dose rifampicin on the PK and PD of nateglinide. Similar to baseline, plasma concentration of nateglinide was higher in CYP2C9*1/*3carriers than CYP2C9*1/*1carriers after multiple-dose rifampicin administration.5. It proved that OATP1B1might be the major transporter of rifampicin and nateglinide in the liver, and rifampicin probably inhibit nateglinide in a competitive way. SLCO1B1521T>C polymorphism significantly weaken the effect of single-dose rifampicin on the PK and PD of nateglinide, however,521T>C had no such effect on multiple-dose rifampicin and nateglimde interaction.Overall, our study provided molecular evidence to the interindividual difference of nateglinide on its disposition, response and drug-drug interaction. Some oral hypoglycemic drugs such as tolbutamide, glimepiride, glibenclamide and glipizide are also metabolized by CYP2C9, our study could provide the useful information for clinical use of antitubercular agent rifampicin and some oral hypoglycemic drugs.