Drug-drug interactions evaluated by a highly active reconstituted native human cytochrome P4503A4 and human NADPH-cytochrome P450 reductase system

Arzneimittelforschung. 2004;54(1):78-83. doi: 10.1055/s-0031-1296940.

Abstract

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.

MeSH terms

  • Antifungal Agents / pharmacology
  • Antimalarials / pharmacology
  • Catalysis
  • Chromatography, High Pressure Liquid
  • Cimetidine / pharmacology
  • Cyclosporine / pharmacology
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions*
  • Electrophoresis, Polyacrylamide Gel
  • Estrogen Antagonists / pharmacology
  • Ethinyl Estradiol / pharmacology
  • Flavanones / pharmacology
  • Hormone Antagonists / pharmacology
  • Humans
  • Immunosuppressive Agents / pharmacology
  • In Vitro Techniques
  • Ketoconazole / pharmacology
  • Microsomes, Liver / enzymology
  • Mifepristone / pharmacology
  • NADPH-Ferrihemoprotein Reductase / metabolism*
  • Phospholipids / chemistry
  • Quinidine / pharmacology
  • Quinine / pharmacology
  • Tacrolimus / pharmacology

Substances

  • Antifungal Agents
  • Antimalarials
  • Estrogen Antagonists
  • Flavanones
  • Hormone Antagonists
  • Immunosuppressive Agents
  • Phospholipids
  • Mifepristone
  • Ethinyl Estradiol
  • Cimetidine
  • Cyclosporine
  • Cytochrome P-450 Enzyme System
  • Quinine
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • NADPH-Ferrihemoprotein Reductase
  • naringenin
  • Quinidine
  • Ketoconazole
  • Tacrolimus