TISSUE AND PERFUSATE PHARMACOKINETICS OF MELPHALAN IN ISOLATED-PERFUSED RAT HINDLIMB

Melphalan is commonly used as a cytotoxic agent in isolated limb perfu sion for locally recurrent malignant melanoma. The time course of melp halan concentrations in perfusate and tissues during a 60-min melphala n perfusion and 30-min drug-free washout in the single-pass perfused r at hindlimb was examined using a physiologically based pharmacokinetic model. The rat hindlimbs were perfused with Krebs-Heinseleit buffer c ontaining 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 at a cons tant rate of 3.8 ml/min. The concentration of melphalan in perfusate a nd tissues was determined by highperformance liquid chromatography. Th e tissue concentrations of melphalan were significantly higher with th e perfusate containing dextran than BSA during the 60-min perfusion. D uring the washout period, the melphalan concentration in the perfusate s decreased rapidly in first few minutes, followed by a slower monoexp onential decline. The estimated half life (t(1/2)) for melphalan remov al from skin and fat was 59 +/- 2 min for both BSA and dextran perfusa tes. However, the estimated t(1/2) for melphalan removal from muscle w as 79 and 96 min for BSA and dextran washout perfusates, respectively. The predicted concentration-time profiles obtained for melphalan with BSA and dextran perfusates appear to correspond closely to the observ ed data. This study showed that the uptake of melphalan into perfused tissues is impaired by the use of perfusates in which melphalan is hig hly bound. Melphalan washout from muscle, but not skin and fat, was fa cilitated by the use of perfusates in which melphalan is highly protei n bound.