title: Physiologically based pharmacokinetics model predicts the lack of inhibition by repaglinide on the metabolism of pioglitazone.
abstract: OBJECTIVE
  Repaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study was to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro, in silico and in vivo.
  
  
  METHODS
  In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE-PBPK linked model was built with Simcyp®. Then, a randomized, 2-phase cross-over clinical study was conducted in 12 healthy volunteers.
  
  
  RESULTS
  Repaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki  = 0.0757 µm), [I]/Ki  > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of pioglitazone in clinical trials showed no significant difference between these two treatment groups (p > 0.05).
  
  
  CONCLUSIONS
  Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo, which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and to the high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro.
authors: Department of Clinical Pharmacy, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors: Qingqing
authors: Q
authors: Xiao
authors: Hangzhou Tigermed Consulting Co., Ltd, Floor17 East, Baoyichuangyi Plaza, No.3760 Nanhuan Road, Beijing District, Hangzhou, Zhejiang, China.
authors: Liling
authors: L
authors: Tang
authors: Department of Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors: Ruijuan
authors: R
authors: Xu
authors: Department of Phase I Drug Clinical Trial, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
authors: Wei
authors: W
authors: Qian
authors: Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors: Jin
authors: J
authors: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D001711:Biotransformation / Q000187:drug effects; D002219:Carbamates / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D019295:Computational Biology; D018592:Cross-Over Studies; D004347:Drug Interactions; D005103:Expert Systems; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D000077205:Pioglitazone; D010880:Piperidines / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D012984:Software; D045162:Thiazolidinediones / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; D045162:Thiazolidinediones; C072379:repaglinide; D000077205:Pioglitazone
keywords: DDIs; IVIVE-PBPK; clinical pharmacokinetics; pioglitazone; repaglinide