The effect of dietary amino acids on the gastrointestinal absorption of melphalan and chlorambucil.

Previous studies have demonstrated that the bioavailability of melphalan and chlorambucil may be reduced under non-fasting conditions, and that the gastrointestinal and cellular absorption of melphalan is an active process, while that of chlorambucil is passive. In view of these findings, the effect of dietary amino acids on the gastrointestinal absorption of these two drugs was investigated using the in situ rat intestine model. The segment lengths used in the study were (mean +/- SD) 47.1 +/- 3.8 cm. Experimentation was carried out in a randomised fashion and involved monitoring the absorption of drug from control intestinal segments and from segments perfused with L-glycine (1 and 10 mM) and L-leucine (1 and 10 mM). For chlorambucil, absorption was carried out from segments perfused with the 10 mM concentration of amino acids only. Aliquots of gut-perfusing solution were removed at 5-min intervals over 30 min and assayed for drug content using a high-performance liquid chromatography (HPLC) method which was selective for each agent. Values recorded for the absorption of melphalan were (mean +/- SD percentage absorption per centimetre segment length over a 30-min period) 1.11% +/- 0.07% cm-1 (control); 1.18% +/- 0.20% cm-1 (1 mM L-glycine); 0.99% +/- 0.27% cm-1 (1 mM L-leucine); 0.80% +/- 0.25% cm-1 (10 mM L-glycine); and 0.60% +/- 0.23% cm-1 (10 mM L-leucine). Chlorambucil absorption from control animals was 1.77% +/- 0.11% cm-1 gut length, as against 1.77% +/- 0.08% cm-1 in 10 mM L-glycine and 1.69% +/- 0.16% cm-1 in 10 mM-L-leucine-perfused segments. The only statistically significant observation was a reduction in melphalan absorption from perfusate containing 10 mM leucine (P less than 0.005). The experimental data suggest that competitive inhibition by amino acids may be one of the mechanisms involved in the observed reduction in melphalan bioavailability under non-fasting conditions, but that it has no effect on chlorambucil absorption.