Effects Of SLCO1B1Gene Polymorphism On Pharmacokinetics Of Repaglinide And Influence Of PPAR-γ2and PTPRD Gene Polymorphisms On Pioglitazone Response

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.