Non-linear pharmacokinetics of high-dose intravenous verapamil

G. Toffoli, I. Robieux, D. Fantin, M. Gigante, S. Frustaci, G. L. Nicolosi, M. De Cicco, M. Boiocchi

Research output: Contribution to journalArticlepeer-review


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 monitoring. We report the pharmacokinetics of escalating doses of verapamil. Methods. We studied nine patients [seven males, two females; median age 46 years (range, 31-57)] with advanced adenocarcinoma of the colon 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-1 h-1), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg h-1). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n = 4) or 60 to 108 h (n = 5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL = ko/C(ss)) and renal clearance (CLr) of verapamil and nor-verapamil. The C(ss) vs rate relationship was fitted to a Michaelis-Menten equation: C(ss) = ko · (k(m) + C(ss))/(V·V(m)). Results. CL was dose-dependent and in all nine patients a significant reduction 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 l h-1 kg-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 and the C(ss) vs rate relationship was best defined by a Michaelis-Menten equation (K(m) = 730 μg 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 metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500-2500 ng ml-1) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.

Original languageEnglish
Pages (from-to)255-260
Number of pages6
JournalBritish Journal of Clinical Pharmacology
Issue number3
Publication statusPublished - 1997


  • Non-linear pharmacokinetics
  • Verpamil

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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