Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics

The time course of tissue levels of melphalan during normothermic isolated limb perfusion, and the overall tissue levels per 60 min of perfusion, were estimated from the known pharmacokinetic parameters for a fixed dose of drug per liter of tissue (Benckhuijsen et al., J. Pharmacol Exp Ther 1986; 237: 583-8). The application of differing total doses of drug resulted in varying concentrations in the perfusate plasma. Above a certain plasma level, uptake into the bulk of the tissues did not increase with the area under the plasma concentration vs time curve or its beta-phase. Similar tissue levels were found after perfusion of regions of less than three and a half liter with 13 mg/l as in regions of 5 to 16 liter after perfusion with 10 mg of melphalan per liter. It cannot be predicted from the available data whether the extent of uptake of melphalan into the tumour tissue is equal to or greater than that into the bulk of the tissues. The estimated uptake of drug into the tissues confirms the validity of the dose calculation per liter of tissue. On the basis of the present results, a refined dosimetric formula will be obtainable that includes the desired area under the plasma concentration vs time curve as a determinant for an optimal dose.