Pharmacokinetics of verapamil and norverapamil during long-term oral therapy.
Serum concentrations of verapamil and its pharmacologically-active metabolite, norverapamil, were measured in six patients with angina at rest after six to fifteen months of therapy. Optimal daily doses were selected during a previous in-hospital titration period and ranged from 240 to 640 mg per day. There was no significant relationship between dose, corrected for body weight, and area under the verapamil serum concentration-time curve (AUC). The mean apparent oral clearance of verapamil was highly variable with a mean of 21.9 +/- 9.1 ml/min/kg and a range of 7.7 to 32.0 ml/min/kg. The ratio of verapamil AUC to norverapamil AUC, used to assess accumulation kinetics of parent drug and metabolite, was less than 1.0 in five of six patient (mean 0.93). However, one patient with verapamil concentrations ranging from 300 to 900 ng/ml had a ratio of 1.37 suggesting saturation of the enzymes that convert verapamil to norverapamil. When the relationship between serum concentration at the end of the dosing interval and angina frequency was studied, it was observed that patients in whom angina was completely suppressed had concentrations greater than 160 ng/ml and patients with poor control (greater than 5 anginal episodes per week) had concentrations less than 60 ng/ml. The findings suggest that the oral clearance of verapamil following long-term (greater than 6 mo.) administration may be different than after short-term therapy and that it is difficult to predict verapamil serum concentrations and antianginal effect during long-term oral therapy. Individualizing verapamil therapy to maintain serum concentrations greater than 100 ng/ml may improve therapeutic response and appears to more reliably predict response than daily dose.
D000368:Aged; D000787:Angina Pectoris / Q000097:blood* / Q000188:drug therapy; D001711:Biotransformation; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D014700:Verapamil / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use
C016904:norverapamil; D014700:Verapamil