Single-dose investigations in healthy subjects have demonstrated substantial impairment of renal and extrarenal clearance of digoxin during coadministration of verapamil. A longitudinal study has been performed to assess the changes in digoxin disposition during long-term verapamil therapy. After one week of verapamil 240 mg/d mean plasma digoxin had risen from 0.21 +/- 0.01 ng/ml (SE) to 0.34 +/- 0.01 ng/ml(p less than 0.01), and renal digoxin clearance had fallen from 197.57 +/- 17.37 ml/min to 128.20 +/- 10.33 ml/min (p less than 0.001). These changes gradually subsided, and after six weeks, renal digoxin clearance had normalized and plasma digoxin had declined to 0.27 +/0 0.02 ng/ml (NS). The 24-h urinary recovery of digoxin increased from 46.46 +/- 3.23% before to 69.78 +/- 3.69% (p less than 0.001) after six weeks of verapamil co-administration, and this elevation persisted throughout the study. The verapamil-induced suppression of renal digoxin elimination disappears over a few weeks of drug exposure, whereas the inhibition of the extrarenal clearance of digoxin seems to persist.