Drug-drug interactions evaluated by a highly active reconstituted native human cytochrome P4503A4 and human NADPH-cytochrome P450 reductase system.
Catalytic activities of native human CYP3A4-mediated reactions as well as drug interactions were directly evaluated by isolated reconstituted human CYP3A4: NADPH-cytochrome P450 reductase systems. The SDS-PAGE pure CYP3A4 and human NADPH-cytochrome P450 reductase had been incorporated into a binary vesicular phospholipid system of dilauroyl-phosphatidyl-choline and phosphatidyl-serine which had proven to achieve optimal nifedipine oxidase activity (19.6 nmol nifedipine oxidized x min(-1) x nmol CYP3A4(-1)). The IC50 values of ketoconazole (CAS 65 277-42-1) (approximately 3 micromol/l), quinidine (CAS 56-54-2) (approximately 5 micromol/l), mifepristone (CAS 84 371-65-3) (-8 micromol/l), 17alpha-ethinylestradiol (CAS 57-63-6) (approximately 17 micromol/l), cimetidine (CAS 51 481-61-9) (approximately 46 micromol/l), FK 506 (tacrolimus) (CAS 104 987-11-3) (approximately 53 micromol/l), naringenin (CAS 480-41-1) (approximately 87 micromol/l), and cyclosporine A (CAS 59 865-13-3) (approximately 90 micromol/l) indicate that all these drugs have an inhibitory effect on nifedipine (CAS 21 829-25-4) metabolism, whereas the drug quinine (CAS 130-95-0) did not elicit any significant inhibition.
Department of Physiological Chemistry, University of Ulm, Ulm, Germany.
Thomas
T
Haehner
Mohamed Osman I
MO
Refaie
Dieter
D
Müller-Enoch
D000935:Antifungal Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D004347:Drug Interactions; D004591:Electrophoresis, Polyacrylamide Gel; D004965:Estrogen Antagonists / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology; D044950:Flavanones / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D015735:Mifepristone / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D000935:Antifungal Agents; D000962:Antimalarials; D004965:Estrogen Antagonists; D044950:Flavanones; D006727:Hormone Antagonists; D007166:Immunosuppressive Agents; D010743:Phospholipids; D015735:Mifepristone; D004997:Ethinyl Estradiol; D002927:Cimetidine; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009251:NADPH-Ferrihemoprotein Reductase; C005273:naringenin; D011802:Quinidine; D007654:Ketoconazole; D016559:Tacrolimus