No abstract

The pharmacokinetics of dacarbazine (DTIC) and its main metabolite 5-aminoimidazole-4-carboxamide (AIC) have been studied in eight patients with malignant melanoma or sarcoma receiving 2.65--6.85 mg DTIC/kg body weight by intravenous bolus injection or by continuous 0.5--6-h infusions on 5 consecutive days. The plasma disappearance of DTIC was biphasic, with a terminal half-life of 41.4 min (range 30.3--51.6 min). The mean distribution volume of DTIC was 0.632 liters/kg and the total clearance was 15.4 ml/kg . min (range 8.7--23.3 ml/kg . min). The renal clearance of DTIC was 5.2--10.9 ml/kg . min, indicating that about 50% of DTIC was eliminated by extrarenal mechanisms. The plasma decay of AIC was mono-exponential with a half-life of 43.0--116 min. A renal clearance of 2.6--5.3 ml/kg . min was calculated for AIC. The urinary recovery was 46%--52% for DTIC and 9%--18% for AIC. The plasma concentrations of DTIC observed during 0.5--6-h infusions of DTIC (5.45--6.85 mg/kg) were 0.66--6.2 micrograms/ml. Comparison of various dosage schedules within the same patient did not reveal relevant differences of the areas under the concentration-time curves. Immunotherapy with Bacillus Calmette-Guérin (BCG) did not significantly influence the pharmacokinetics of DTIC. During isolated extremity perfusion with DTIC (75--130 mg/kg extremity) for treatment of malignant tumors of the extremities concentrations of DTIC ranged from 150--500 micrograms/ml perfusate. There was no evidence of AIC formation. In isolated liver perfusion experiments in anesthetized dogs metabolic degradation of DTIC to AIC was demonstrated.