The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m2 over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m2. Total melphalan clearance after the 5 mg/m2 dose ranged from 66.0 to 272 ml/min per m2; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m2; the fraction unbound in plasma, from 0.0598 to 0.460; and t1/2 beta, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m2 and 15 to 961 ml/min per m2 respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose excreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.

Melphalan uptake in the intestine has recently been shown to be an energy-dependent process which is affected by metabolic inhibitors. It is therefore theoretically possible that amino acids in food could reduce melphalan absorption by competing for uptake at the sites of absorption in the intestine. Since L-leucine has been shown to be the most potent inhibitor of melphalan transport into cells in vitro, this amino acid was chosen for the present study in patients. Oral melphalan (4.5 +/- 0.5 mg/m2) was given to ten fasting patients with and without a 2-g oral dose of L-leucine on separate randomized occasions at least 1 week apart. Melphalan plasma levels were measured by high-performance liquid chromatography (HPLC) for 5-h after dosing. L-Leucine plasma levels were measured by HPLC before and at 1 h after dosing. The area under the curve for melphalan was lower in seven of the patients after L-leucine. Plasma L-leucine levels 1 h after melphalan administration were 15.4 +/- 3.7 micrograms/ml fasting and 35.4 +/- 5.2 micrograms/ml after L-leucine. The results indicate that L-leucine can reduce plasma melphalan levels in some patients, probably through a reduction in absorption of the drug from the gastrointestinal tract. However, the effect, like that of food, is highly variable.

No abstract