NONLINEAR PHARMACOKINETICS OF HIGH-DOSE INTRAVENOUS VERAPAMIL

Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic m onitoring. We report the pharmacokinetics of escalating doses of verap amil. Methods We studied nine patients [seven males, two females, medi an age 46 years (range, 31-57)] with advanced adenocarcinoma of the co lon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg(-1) followed by 12 h continuous i.v. infusion at 0.20 mg kg h(-1)), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg(-1) h(-1). The highest rate wa s maintained for 48 h. Doxorubicin was given as a continuous i.v. infu sion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and ur ine collections were taken every 12 h. Verapamil and nor-verapamil wer e assayed by high performance liquid chromatography. We calculated sys temic clearance of verapamil (CL = ko/C-ss) and renal clearance (CLr) of verapamil and nor-verapamil. The C-ss vs rate relationship was fitt ed to a Michaelis-Menten equation: C-ss = ko.(K-m + C-ss)/(V.V-m). Res ults CL was dose-dependent and in all nine patients a significant redu ction in CL was observed over the dose range (mean CL +/- s.d. were 0. 51 +/- 0.31, 0.38 +/- 0.16, 0.32 +/- 0.18, and 0.27 +/- 0.11 1 h(-1) k g(-1), respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg(-1) h(-1); P = 0.0001). C-ss increased more than proportionally to the dose rate an d the C,, vs rate relationship was best defined by a Michaelis-Menten equation (K-m = 730 mu g l(-1); V.V-m = 0.55 mg kg(-1) h(-1)), (r = 0. 994; P = 0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose. Conclusions These findings suggest a non-linear, capacity-limited meta bolic clearance of high-dose verapamil. Using escalating infusion rate s, high verapamil concentrations (1500-2500 ng mi) were achieved witho ut major toxicity. Saturable clearance may cause higher bioavailabilit y and slower elimination of verapamil after acute oral overdoses.