Systemic thermochemotherapy: toxicity and plasma pharmacokinetics of methotrexate and doxorubicin

Chemotherapy administered during systemic hyperthermia is more tumoricidal than either modality used alone. The purpose of this study was to evaluate plasma drug pharmacokinetics and host toxicity when methotrexate (MTX) or doxorubicin (adriamycin--ADR) was given at 37 or 43 degrees C. Eight dogs were heated to 43 degrees C for 1 hr without chemotherapy; eight dogs received MTX (5 mg/kg) and four dogs received ADR (2 mg/kg) intravenously as a constant infusion at 43 or 37 degrees C. Blood samples were obtained at 0, 1, 2, 24, and 48 hr. Mean plasma MTX levels were not significantly different at 1, 2, and 6 hours in 43 and 37 degrees C dogs, but at 24 and 48 hr mean plasma MTX levels were significantly elevated in heated (43 degrees C) dogs compared with sham-heated (37 degrees C) dogs. Plasma MTX concentration multiplied by time (area under curve) was 131 g . hr/liter in 43 degrees C dogs compared with 73 g . hr/liter in 37 degrees C dogs (P less than 0.001). Vomiting and bloody diarrhea lasted an average of 4 days in heated control dogs (no drugs) 4 days in 37 degrees C dogs, and 5 to 7 days in 43 degrees C MTX dogs. Mean plasma ADR levels were similar in 37 and 43 degrees C dogs at all time intervals. Vomiting and bloody diarrhea lasted at least 7 days in 43 degrees C dogs compared with only 1 day in 37 degrees C dogs treated with ADR.(ABSTRACT TRUNCATED AT 250 WORDS)