Pharmacokinetic Interactions Affecting the Antidiabetic Repaglinide

I N T R O D U C T I O N ..........................................................................11 R E V I E W O F T H E L I T E R A T U R E ............................................12 1 Drug interactions .............................................................................12 1.1 Pharmacokinetic drug interactions ............................................12 1.2 Pharmacodynamic drug interactions..........................................13 2 Drug metabolism and transport..........................................................14 2.1 CYP enzyme system ...............................................................14 2.2 Conjugating enzymes .............................................................24 2.3 Drug transporters ..................................................................24 3 In vitro studies on drug metabolism ...................................................28 3.1 In vitro systems.....................................................................28 3.2 Enzyme kinetics .....................................................................29 3.3 Identification of CYP enzymes responsible for drug metabolism ....30 3.4 Characterising the inhibitory properties of drugs.........................30 3.5 In vitro-in vivo extrapolation ...................................................31 4 Repaglinide in the treatment of type 2 diabetes....................................33 4.1 Treatment principles of type 2 diabetes mellitus .........................33 4.2 Repaglinide ...........................................................................34 5 Drugs studied with repaglinide in vivo.................................................38 5.1 Bezafibrate and fenofibrate (Study II).......................................38 5.2 Trimethoprim (Study III) ........................................................38 5.3 Cyclosporine (Study IV) ..........................................................38 5.4 Telithromycin (Study V) ..........................................................39 5.5 Montelukast (Study V) ............................................................39 5.6 Pioglitazone (Study VI) ...........................................................40 A I M S O F T H E S T U D Y...............................................................42 M A T E R I A L S A N D M E T H O D S..................................................43 1 In vitro studies ................................................................................43 1.1 Design of in vitro studies.........................................................43 1.2 Determination of drug concentrations .......................................45 1.3 Data analysis.........................................................................45 2 In vivo studies.................................................................................47 2.1 Design of in vivo studies .........................................................47 2.2 Subjects ...............................................................................47 2.3 Blood sampling ......................................................................47 2.4 Determination of drug concentrations .......................................49 2.5 Pharmacokinetic calculations ...................................................50 2.6 Pharmacodynamic variables.....................................................50 2.7 Genotyping ...........................................................................51