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 journalArticle

8 Citations (Scopus)

Abstract

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
Volume44
Issue number3
Publication statusPublished - 1997

Fingerprint

Verapamil
Pharmacokinetics
Intravenous Infusions
Doxorubicin
Kidney
Urine Specimen Collection
Multiple Drug Resistance
Biological Availability
Colon
Adenocarcinoma
Hemodynamics
High Pressure Liquid Chromatography

Keywords

  • Non-linear pharmacokinetics
  • Verpamil

ASJC Scopus subject areas

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

Cite this

Toffoli, G., Robieux, I., Fantin, D., Gigante, M., Frustaci, S., Nicolosi, G. L., ... Boiocchi, M. (1997). Non-linear pharmacokinetics of high-dose intravenous verapamil. British Journal of Clinical Pharmacology, 44(3), 255-260.

Non-linear pharmacokinetics of high-dose intravenous verapamil. / Toffoli, G.; Robieux, I.; Fantin, D.; Gigante, M.; Frustaci, S.; Nicolosi, G. L.; De Cicco, M.; Boiocchi, M.

In: British Journal of Clinical Pharmacology, Vol. 44, No. 3, 1997, p. 255-260.

Research output: Contribution to journalArticle

Toffoli, G, Robieux, I, Fantin, D, Gigante, M, Frustaci, S, Nicolosi, GL, De Cicco, M & Boiocchi, M 1997, 'Non-linear pharmacokinetics of high-dose intravenous verapamil', British Journal of Clinical Pharmacology, vol. 44, no. 3, pp. 255-260.
Toffoli G, Robieux I, Fantin D, Gigante M, Frustaci S, Nicolosi GL et al. Non-linear pharmacokinetics of high-dose intravenous verapamil. British Journal of Clinical Pharmacology. 1997;44(3):255-260.
Toffoli, G. ; Robieux, I. ; Fantin, D. ; Gigante, M. ; Frustaci, S. ; Nicolosi, G. L. ; De Cicco, M. ; Boiocchi, M. / Non-linear pharmacokinetics of high-dose intravenous verapamil. In: British Journal of Clinical Pharmacology. 1997 ; Vol. 44, No. 3. pp. 255-260.
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abstract = "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.",
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T1 - Non-linear pharmacokinetics of high-dose intravenous verapamil

AU - Toffoli, G.

AU - Robieux, I.

AU - Fantin, D.

AU - Gigante, M.

AU - Frustaci, S.

AU - Nicolosi, G. L.

AU - De Cicco, M.

AU - Boiocchi, M.

PY - 1997

Y1 - 1997

N2 - 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.

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