High-throughput screening for the assessment of time-dependent inhibitions of new drug candidates on recombinant CYP2D6 and CYP3A4 using a single concentration method

Xenobiotica. 2004 Jan;34(1):87-101. doi: 10.1080/00498250310001630206.

Abstract

1. The inhibitory effects of various test compounds on recombinant human CYP3A4 activity assayed by fluorescent metabolite formation from 7-benzyloxyquinoline (7-BQ) and the effect of pre-incubation on inhibition were evaluated using the microtitre plate assay with multiple concentrations of test compounds (multiple concentration method). 2. Among the test compounds studied, ketoconazole inhibited CYP3A4 activity most extensively, followed by miconazole, troleandomycin, terfenazine and midazolam. The IC(50) values of other compounds exceeded 10 microM, but those of many compounds decreased after pre-incubation. The inhibitory effects of verapamil, amiodarone and diltiazem after pre-incubation were 205, 154 and 833 times greater than those in the case of co-incubation, respectively. 3. To assess the inhibitory effects more readily, the validity of the microtitre plate assay with a single concentration of the test compound (single concentration method) was studied. The accuracy of the automated dispensation and the coefficient of variation on enzyme activity were approximately 3%. 4. The IC(50) values estimated using the per cent of residual activity from the single concentration method matched closely those from the multiple concentration method. When the IC(50) value as inhibitor concentration was used for a single concentration method, the method enabled easy estimation of inhibitory patterns (such as competitive or time-dependent inhibition) on cytochromes P450. Therefore, from the ease of the technique, automation of the microtitre plate assay and application of the single concentration method might be useful for inhibitory assessment of cytochromes P450 more than that of current conventional methods.

Publication types

  • Comparative Study

MeSH terms

  • Amiodarone / pharmacology
  • Animals
  • Baculoviridae
  • Binding, Competitive
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Diltiazem / pharmacology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fluorescence
  • Humans
  • Inhibitory Concentration 50
  • Ketoconazole / pharmacology
  • Miconazole / pharmacology
  • Midazolam / pharmacology
  • Propafenone / pharmacology
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Troleandomycin / pharmacology
  • Verapamil / pharmacology

Substances

  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Quinolines
  • Recombinant Proteins
  • 7-benzyloxyquinoline
  • Propafenone
  • Miconazole
  • Cytochrome P-450 Enzyme System
  • Troleandomycin
  • Verapamil
  • CYP3A protein, human
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Diltiazem
  • Amiodarone
  • Midazolam
  • Ketoconazole