Risk Panel Completed

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 gM. 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 < 100 mmHg or a fall in systolic BP of > 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 (> 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 gM 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 ILM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support. Resistance to cytotoxic agents is a common cause of failure of therapy in both solid tumours and haematological malig-nancies and there is evidence that expression of the multi-drug resistance (MDR) phenotype underlies drug resistance in some tumours (Goldstein et al., 1989). Although several years have elapsed since the observation that verapamil reduces resistance to vincristine and doxorubicin in certain cell lines (Tsuruo et al., 1982), its role in clinical oncology is still uncertain. The modulation of drug resistance by vera-pamil appears independent of calcium channel blockage (Gruber et al., 1988) and is at least in part due to its binding to the P170 glycoprotein with reduction of drug efflux from cells via this energy dependent pump (Chen et al., 1986; Moscow et al., 1988). In vitro studies show a dose response relationship with maximal reduction of resistance with 6 gM verapamil (Plumb et al., 1990) but clinical experience of verapamil in …