SEMMELWEIS UNIVERSITY DOCTORAL SCHOOL OF PHARMACEUTICAL SCIENCES INFLUENCE OF DIABETES ON CYTOCHROME P450 ENZYME MEDIATED DRUG METABOLISM – CASE STUDIES ON DICLOFENAC AND K-48 Ph.D. Thesis

ABBREVIATIONS ADME adsorption, distribution, metabolism, elimination ADP adenosine diphosphate AGGTCA adenine-guanine-guanine-thymine-cytosine-adenine AhR aryl hydrocarbon receptor Ala alanine (amino acid) Amu atomic mass unit Arg arginine (amino acid) Arnt aryl hydrocarbon receptor nuclear translocator Asn asparagine (amino acid) ATP adenosine triphosphate AUC area under the plasma concentration-time curve BBB blood brain barrier BZY benzydamine BZYNO benzidamine N-oxide Ca 2+ calcium ion cAMP cyclic adenosine monophosphate CAR constitutive androstane receptor cDNA complementary deoxyribonucleic acid CL clearance CL int intrinsic clearance CL nr nonrenal clearance CL r renal clearance CSF cerebrospinal fluide Ct threshold cycle CYP cytochrome P450 D55 55 mg/kg streptozotocin treated diabetic rats D70 70 mg/kg streptozotocin treated diabetic rats DAB 3,3'-diaminobenzidine DNA deoxyribonucleic acid EDTA ethylenediamine-tetraacetic acid FAD flavin adenine dinucleotide FMO flavin-containing monooxygenase FXRα farnesoid x receptor GADPH glyceraldehyde-3-phosphate dehydrogenase Gly glycine (amino acid) GR glucocorticoid receptor GRE glucocorticoid response element HNF-1α hepatic nuclear factor – 1α HNF-4α hepatic nuclear factor – 4α HPLC high performance liquid chromatography HPLC-ECD high performance liquid chromatography with electrochemical detector HPLC-MS high performance liquid chromatography with mass spectrometry i.m. intramuscular i.p. intraperitoneal ID55 insulin treated 55 mg/kg streptozotocin induced diabetic rats 5 ID70 insulin treated 70 mg/kg streptozotocin induced diabetic rats IDDM insulin-dependent diabetes mellitus K M Michaelis constant LXRα liver X receptor α Lys lysine (amino acid) MGB minor groove binder mRNA messenger ribonucleic acid NADPH nicotinamide adenine dinucleotide phosphate, reduced NIDDM non-insulin-dependent diabetes mellitus NSAID non-steroidal anti-inflammatory drug OP organophosphonates p.o. per os P450 cytochrome P450 PACER pyridinium aldoxime cholinesterase reactivator PAH polycyclic aromatic hydrocarbon PCN pregnenolon 16-carbonitrile PKA cAMP dependent protein kinase A PMSF phenylmethanesulphonyl fluoride PPARα peroxisome proliferator activated receptor α PXR pregnane X receptor RAR retinoic acid receptor RNA ribonucleic acid RQ relative quantitation RT retention time RXRα retinoid X receptor α S.D. standard deviation SIM single ion monitoring STZ streptozotocin TBS Tris buffer solution TCA trichloroacetic acid TCDD 2,3,7,8-tetrachlorodibenzo –p-dioxin TRIS tris hydroxymethyl aminomethane Tyr tyrosine (amino acid) VDR vitamin D receptor V max maximum velocity Vss volume of distribution at steady state YY1 zinc finger protein 6 1. INTRODUCTION In the process of drug candidate screening and development in vitro drug metabolism studies are aimed at the evaluation of the potential for metabolism based drug interactions. The bioavailability of orally administered drugs is determined mainly by the first pass effect of the liver; however, the barrier function of the small intestine is also essential. Any alteration …