Combination chemotherapy with adriamycin and streptozotocin; II. Clinicopharmacologic correlation of augmented adriamycin toxicity caused by streptozotocin

Abstract

Plasma pharmacokinetics were compared in patients with advanced sarcomas receiving adriamycin, 60 mg/m² intravenously (iv) on day 1 every 3 wk in combination with streptozotocin, 500 mg/m²/day iv on days 1 to 5 every 3 wk, and patients receiving adriamycin alone in the same dose and schedule. The combination-treated group had greater adriamycin drug exposure (concentration × time) when serial plasma levels were analyzed by fluorescence assay and by radioimmunoassay (RlA). The plasma t^½ of adriamycin equivalents measured by fluorescence assay was also significantly prolonged in the combination-treated group. These changes correlated welt with an increase in adriamycin-related toxicity—mucositis and myelosuppression—seen in the patients who received the combination drug therapy. Plasma streptozotocin kinetics and the incidence of streptozotocin-related side effects—hepatic and renal function abnormalities—were those published for streptozotocin alone. Evidence is presented to support the hypothesis that the increased incidence of adriamycin side effects is due to streptozotocin-related hepatic dysfunction, affecting both the detoxification and excretion of adriamycin. Combination of other drugs with adriamycin should take into account their potential for inducing hepatic dysfunction which may affect the therapeutic index of adriamycin.