title: Pharmacokinetic and pharmacodynamic interaction trial after repeated oral doses of imidapril and digoxin in healthy volunteers.
abstract: OBJECTIVE
  To investigate the potential pharmacokinetic and pharmacodynamic interaction between imidapril and digoxin.
  
  
  METHODS
  AUC, Cmax and t(max) of imidapril, imidaprilat and digoxin were calculated and evaluated in a randomized, doubleblind three-period cross-over design in 12 healthy volunteers after 8 days treatment with the following combinations: digoxin 0.25 mg day(-1) + placebo (D + P); imidapril 10 mg day(-1) + placebo (I + P); imidapril 10 mg day)(-1) + digoxin 0.25 mg day(-1) (I + D).
  
  
  RESULTS
  Mean AUC (0, 24 h) of digoxin was 10.4 (+/- 4.9 s.d.) ng ml(-1) h (D + P) and 10.7 (+/- 3.9 s.d.) ng ml(-1) h (I + D), respectively (90%-confidence intervals [CI] for the ratio of (D + P) and (I + D): 0.91-1.27, point estimator [PE]: 1.06). Mean AUC (0, 24 h) of imidapril was 133 (+/- 86 s.d.) ng ml(-1) h (I + P) and 108 (+/- 52 s.d.) ng ml(-1) h (I + D), respectively (90%-CI: 0.76-0.94, PE 0.85). AUC (0, 24 h) of imidaprilat was 215 (+/- 91 s.d.) ng ml(-1) h (I + P) and 194 (+/- 54 s.d.) ng ml(-1) h (I + D), respectively (90%-CI: 0.80-1.08, PE 0.93). Cmax was 19.9 (+/- 8.7 s.d.) ng ml(-1) (I + P) and 15.9 (+/- 5.3 s.d.) ng ml(-1) (I + D) (90%-CI: 0.67-1.00, PE 0.82). The results indicate a slight reduction of imidapril and imidaprilat plasma levels when coadministered with digoxin without any effect on digoxin plasma levels. Maximal ACE-inhibition was 79% (I + P) and 67% (I + D).
  
  
  CONCLUSIONS
  Grouped data analysis of imidaprilat plasma levels vs ACE-activity showed that for maximal inhibition of plasma ACE activity, imidaprilat plasma levels should exceed 10 ng ml(-1). Under digoxin and imidapril, more plasma concentrations of imidaprilat were seen under this level as after imidapril alone, this reduces the integral of the ACE-inhibition/time curves by about 20 to 30%.
authors.affiliation: Institute of Clinical Pharmacology, University Hospital Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Harder
authors.forename: P A
authors.initials: PA
authors.lastname: Thürmann
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D048289:Imidazolidines; D011863:Radioimmunoassay
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D048289:Imidazolidines; D004077:Digoxin; C065166:imidapril; C078006:imidaprilat