Pharmacokinetics of melphalan in isolated limb perfusion

The pharmacokinetics of melphalan was studied by sampling of tissue and pla sma in 72 rats that underwent isolated hyperthermic limb perfusion under di fferent conditions. A miniaturized extracorporeal circulation system for sm all animals was used for perfusion of the rat hindlimb. Melphalan levels (L -phenylalanine mustard, L-PAM) were determined by high-performance liquid c hromatography (HPLC). The temperature of the perfusate plasma and tissue, p H, administration method, and flow rate were modified and compared with reg ard to their influence on pharmacokinetic parameters. The highest tissue pe netration of melphalan was observed under the following conditions: (a) pH range of the perfusate plasma between 7.3 and 7.7 (physiological environmen t), (b) temperature range of the perfusate from 40 degrees to 41.5 degrees C (destruction of cellular carrier systems at higher temperatures and incre ased inactivation by hydrolysis of melphalan above 41.5 degrees C), (c) app lication of melphalan as a single dose into the reservoir of the extracorpo real circuit (optimal tissue penetration), and (d) reduced perfusate flow ( prolonged contact time between perfusate and tissue).