Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data

Xenobiotica. 2004 Mar;34(3):215-28. doi: 10.1080/00498250310001649341.


1: The inhibition kinetics of eplerenone (EP) 6beta-hydroxylation by 10 drugs were determined in vitro using human liver microsomes. Inhibition factors were calculated from in vitro inhibition constant (Ki) and three different inhibitor Cmax values (liver Cmax of total and unbound inhibitor, and maximum influx concentration of inhibitor into the liver). Subsequently, the inhibition factors were compared with available pharmacokinetic data derived from clinical interaction trials conducted by Pfizer involving EP and these drugs. EP was also evaluated for its effect on the metabolism of 10 drugs in vitro, and again the in vitro data were compared with results from the clinical trials. 2: The Ki values for the inhibition of EP 6beta-hydroxylation by cisapride, cyclosporine, digoxin, erythromycin, fluconazole, ketoconazole, midazolam, saquinavir, simvastatin and verapamil were 2.90, 1.24,>75.0, 9.50, 59.0, 0.160, 8.10, 0.546, 6.23 and 13.3 microM, respectively. Among the three methods, inhibition factors (Rb) calculated using the Ki and estimated liver Cmax values of the unbound drug were best correlated with the in vivo area under the curve-fold increases of EP in humans. The Rb values for the drugs listed above were 1.04, 1.69, 1.00, 2.17, 2.24, 4.90, 1.00, 1.82, 1.01 and 1.04, respectively, and the in vivo area under the curve-fold increases of EP by these drugs were 1.04, 1.16, 0.930, 2.87, 2.24, 5.39, 1.00, 2.07, 1.03 and 1.98, respectively. 3: EP did not have any significant effects on the drugs tested in vitro or in the clinic. 4: Using in vitro metabolic interaction data, human in vivo pharmacokinetic interactions involving EP could be predicted nearly quantitatively. The lack of effects of EP on the pharmacokinetics of other drugs in man was also suggested in the in vitro data.

MeSH terms

  • Drug Antagonism
  • Eplerenone
  • Humans
  • Hydroxylation / drug effects
  • In Vitro Techniques
  • Microsomes, Liver / metabolism*
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics
  • Spironolactone / analogs & derivatives*
  • Spironolactone / metabolism*
  • Spironolactone / pharmacokinetics


  • Pharmaceutical Preparations
  • Spironolactone
  • Eplerenone