title: Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone.
abstract: OBJECTIVE
  To examine the possible interaction of the calcium channel blockers diltiazem and mibefradil with orally administered methylprednisolone.
  
  
  METHODS
  In this randomized, double-blind, placebo-controlled, three-phase crossover study, nine healthy SUBJECTS received 60 mg diltiazem three times a day, 50 mg mibefradil once a day, or placebo orally for 3 days. On day 3, each subject received a 16-mg oral dose of methylprednisolone. Plasma concentrations of methylprednisolone and cortisol were determined by HPLC up to 47 hours.
  
  
  RESULTS
  Compared with placebo, diltiazem and mibefradil increased the total area under the plasma concentration-time curve of methylprednisolone [AUC(0-infinity)] 2.6-fold (P < .001) and 3.8-fold (P < .001), the peak plasma concentration 1.6-fold (P < .001) and 1.8-fold (P < .001), and the elimination half-life 1.9-fold (P < .001) and 2.7-fold (P < .001), respectively. The nighttime exposure to methylprednisolone [AUC(12-23)] was increased 28.2-fold (P < .01) and 72.1-fold (P < .001) by diltiazem and mibefradil, respectively, and correlated negatively (r = -0.81, P < .001) with the morning plasma cortisol concentration (measured at 8 AM, 23 hours after the administration of methylprednisolone). During the diltiazem phase, the morning plasma cortisol concentration was 12% of that during the placebo phase (P < .001); during the mibefradil phase, the morning plasma cortisol concentration was 2% of that during the placebo phase (P < .001).
  
  
  CONCLUSIONS
  Coadministration of diltiazem or mibefradil with methylprednisolone resulted in increased plasma concentrations and a greatly enhanced adrenal-suppressant effect of oral methylprednisolone. Care should be taken if methylprednisolone is coadministered with a potent CYP3A4 inhibitor for a long period.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Varis
authors.forename: J T
authors.initials: JT
authors.lastname: Backman
authors.forename: K T
authors.initials: KT
authors.lastname: Kivistö
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D020748:Mibefradil / Q000008:administration & dosage / Q000494:pharmacology*; D012016:Reference Values
chemical_list: D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D020748:Mibefradil; D004110:Diltiazem; D006854:Hydrocortisone; D008775:Methylprednisolone