Abstract
The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bissett, D., Kerr, D., Cassidy, J. et al. Phase I and pharmacokinetic study of D-verapamil and doxorubicin. Br J Cancer 64, 1168–1171 (1991). https://doi.org/10.1038/bjc.1991.484
Issue Date:
DOI: https://doi.org/10.1038/bjc.1991.484
This article is cited by
-
Inhibitory effect of calcium channel blockers on human mesangial cell growth: Evidence for actions independent of L-type Ca2+ channels
Kidney International (1996)
-
Die Hemmung des P-Glykoprotein-mediierten, transepithelialen Zytostatikatransportes durch R-Verapamil, Cyclosporin SDZ PSC-833 und Tamoxifen in einem Adenokarzinom-Monolayer-Modell
European Surgery (1995)
-
Establishment and characterization of a multidrug-resistant human bladder carcinoma cell line RT112/D21
Urological Research (1995)
-
In vitro effect of r-verapamil on acute myelogenous leukemia blast cells: studies of cytokine secretion and cytokine-dependent blast proliferation
Cancer Chemotherapy and Pharmacology (1995)
-
Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma
Journal of Cancer Research and Clinical Oncology (1995)