Studies on the mechanism of gastrointestinal absorption of melphalan and chlorambucil.

The uptake of melphalan into tumour cells has been shown previously to involve active transport, while that of chlorambucil is by passive diffusion. In view of these findings, the mechanism of their gastrointestinal absorption was investigated using the in situ rat intestinal model. Segment lengths in all cases were (mean +/- SD) 47.2 +/- 4.7 cm. Drug absorption was monitored from control intestinal segments and from segments pretreated with the metabolic inhibitors 2,4 dinitrophenol (DNP) or carbonylcyanide-M-chlorophenyl-hydrazone (CCCP). Aliquots of gut-perfusing solution were removed at 5-min intervals over 30 min and assayed for drug using a high-performance liquid chromatography (HPLC) method selective for the alkylating agents. Absorption of melphalan by control animals was (mean +/- SD) 1.22% +/- 0.25% cm-1 gut length, as against 0.59% +/- 0.13% cm-1 in DNP- and 0.45% +/- 0.07% cm-1 in CCCP-treated animals. Absorption of chlorambucil was 1.47% +/- 0.17% cm-1 (control), 1.49% +/- 0.06 cm-1 (DNP), and 1.58% +/- 0.23% cm-1 (CCCP). It was clear, therefore, that pretreatment of intestinal segments with metabolic inhibitors led to a reduced absorption of melphalan (P less than 0.01) but did not influence that of chlorambucil. The experimental data suggest that melphalan uptake from the intestine involves an energy-dependent system whereas chlorambucil is passively absorbed.