title: Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide.
abstract: OBJECTIVE
  Quantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide.
  
  
  METHODS
  In vitro hepatic transport of repaglinide, gemfibrozil and gemfibrozil 1-O-β-glucuronide was characterized using sandwich-culture human hepatocytes. A PBPK model, implemented in Simcyp (Sheffield, UK), was developed utilizing in vitro transport and metabolic clearance data.
  
  
  RESULTS
  In vitro studies suggested significant active hepatic uptake of repaglinide. Mechanistic model adequately described repaglinide pharmacokinetics, and successfully predicted DDIs with several OATP1B1 and CYP3A4 inhibitors (<10% error). Furthermore, repaglinide-gemfibrozil interaction at therapeutic dose was closely predicted using in vitro fraction metabolism for CYP2C8 (0.71), when primarily considering reversible inhibition of OATP1B1 and mechanism-based inactivation of CYP2C8 by gemfibrozil and gemfibrozil 1-O-β-glucuronide.
  
  
  CONCLUSIONS
  This study demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide. The model quantitatively predicted several repaglinide DDIs, including the complex interactions with gemfibrozil. Both OATP1B1 and CYP2C8 inhibition contribute significantly to repaglinide-gemfibrozil interaction, and need to be considered for quantitative rationalization of DDIs with either drug.
authors: Pharmacokinetcis, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut, USA. manthena.v.varma@pfizer.com
authors: Manthena V S
authors: MV
authors: Varma
authors: Yurong
authors: Y
authors: Lai
authors: Emi
authors: E
authors: Kimoto
authors: Theunis C
authors: TC
authors: Goosen
authors: Ayman F
authors: AF
authors: El-Kattan
authors: Vikas
authors: V
authors: Kumar
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002219:Carbamates / Q000493:pharmacokinetics* / Q000494:pharmacology; D002460:Cell Line; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions; D015248:Gemfibrozil / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D002219:Carbamates; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D010880:Piperidines; C503999:SLCO1B1 protein, human; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil