Pharmacokinetics of dacarbazine (DTIC) and its metabolite 5-aminoimidazole-4-carboxamide (AIC) following different dose schedules

Summary 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 g/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 g/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.AD will present this work as part of her thesis to the Faculty of Medicine of the Justus Liebig-Universität, Giessen, Federal Republik of Germany