Alteration in Epirubicin Pharmacokinetics and Metabolism by Dexverapamil: Results from a Phase II Study in Patients with Metastatic Breast Cancer

Abstract

Background: To study the effect of the resistance-modifying agent (RMA) dexverapamil on the pharmacokinetics and metabolism of epirubicin. Methods: Nine women with metastatic breast cancer who received epirubicin (120 mg/m 2 ) as a 0.25-hour infusion without dexverapamil during the first treatment cycle and with dexverapamil (12 × 300 mg p. o. every 6 h) during the third treatment cycle were monitored with frequent plasma samples up to 48 h postinfusion. Epirubicin and its metabolites and dexverapamil and its main metabolite nordexverapamil were measured using a reverse-phase high-pressure liquid chromatography assay. Results: The concomitant administration of dexverapamil resulted in an increase in mean (±SD) epirubicin clearance from 1,408 (610) ml/min/m 2 to 2,004 (1,696) ml/min/m 2 , a decrease in epirubicin exposure (area under the curve (AUC)) from 2,968 (1,219) mg × h/ml to 1,901 (494) mg × h/ml, and an increase of the volume of distribution at steady state from 1,436 (1,231) l/m 2 to 2,425 (1,340) l/m 2 . The mean residence time and the elimination half-life were not different. There was a significant increase of epiglucuronide and the 7-deoxy-aglycones. At the time of epirubicin administration mean dexverapamil and nordexverapamil plasma levels were 790±409 and 755 ± 274 ng/ml, respectively. Conclusion: Dexverapamil had a significant effect on the pharmacokinetics and metabolism of epirubicin. However, other than observed in previous studies of RMAs and cytotoxic drugs, dexverapamil did not increase but reduce the AUC of epirubicin and had no effect on its toxicity. These data suggest that the type of pharmacologic interaction between RMAs and cytotoxic drugs can differ depending on the particular compounds used in combination.

Nonionic surfactants modulate the transport activity of ATP-binding cassette (ABC) transporters and solute carriers (SLC): Relevance to oral drug absorption

“…Therefore, inhibitors of efflux transporters such as P-gp and BCRP were then identified and these inhibitors, for example verapamil (Tsuruo et al, 1981), dexverapamil (Gramatté andOertel, 1999), valspodar (vanAsperen et al, 1997), and GF120918 (Hyafil et al, 1993), showed promising results in inhibiting P-gp (GF120918 also inhibited BCRP) (Maliepaard et al, 2001a), in pre-clinical studies. However, this strategy failed to produce safe and effective treatment in human clinical trials (Dalton et al, 1995;Greenberg et al, 2004;Lehnert et al, 1998;Mross et al, 1999;Planting et al, 2005;Ries and Dicato, 1991;Sparreboom et al, 1999;Warner et al, 1998). Subsequently, other strategies based on natural products (Appendino et al, 2003;Yoshida et al, 2005) and pharmaceutical excipients (Lo, 2003;Rege et al, 2002;Regev et al, 1999;Zhang et al, 2003) were suggested.…”