title: Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction.
abstract: OBJECTIVE
  A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms.
  
  
  METHODS
  In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg x kg(-1) digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay.
  
  
  RESULTS
  Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) +/- SD 23 +/- 5.2 vs. 14 +/- 2.9 microg x L(-1) x h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) +/- SD 34 +/- 39 vs. 57 +/- 41 mL min-1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin.
  
  
  CONCLUSIONS
  Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.forename: Christoph
authors.initials: C
authors.lastname: Göggelmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Jochen
authors.initials: J
authors.lastname: Ludwig
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Walter-Sack
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004311:Double-Blind Method; D004347:Drug Interactions; D019450:Genes, MDR / Q000235:genetics; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D004077:Digoxin; D003404:Creatinine; D017291:Clarithromycin