Melphalan has been reported to be actively transported into tumor cells by two amino acid carrier systems. As amino acids are transported across cerebral capillaries by a facilitated mechanism, studies were undertaken to assess whether or not melphalan was transported similarly, and additionally to determine melphalan's plasma and brain pharma-cokinetics. The brain uptake of [14C]melphalan was measured by an in situ brain perfusion technique in the anesthetized rat utilizing [14C]melphalan. The cerebrovascular permeability-surface area product of [14C]melphalan was calculated at cold melphalan concentrations from 0 to 16.3 µmol/ml. The permeability-surface area product was concentration dependent and decreased from 10.8 ± 0.6 (±SE) × 10-4s-1 at 0.02 µmol/ml melphalan to 5.4 ± 0.3 × 10-4s-1 at 16.3 µmol/ml. The system became saturated at a concentration in excess of 0.1 µmol/ml. The Michaelis-Menten parameters Vmax and Km, determined by nonlinear regression analysis of the permeability-surface area product data, equaled 0.9 ± 0.3 × 10-4 µmol/s/g and 0.15 ± 0.06 µmol/ml, respectively, for the saturable component of melphalan's brain uptake. The Kd of the nonsaturable component was 5.3 ± 0.03 × 10-4s-1. Addition of the amino acid l-phenylalanine to the brain perfusate inhibited the saturable component of melphalan's brain uptake. The analysis of the plasma and brain concentrations of melphalan by high-performance liquid chromatography, following i.v. melphalan administration, demonstrated that approximately 15% of the drug that was present in plasma entered the brain. These data suggest that the brain uptake of melphalan is facilitated, demonstrating concentration-dependent uptake, saturation, and inhibition, and that melphalan shares the large neutral amino acid carrier system at the blood-brain barrier.
↵1 To whom requests for reprints should be addressed, at Laboratory of Neurosciences, Building 10, Room 6C 103, NIH, Bethesda, MD 20892.
- Received August 25, 1986.
- Revision received December 3, 1986.
- Accepted December 5, 1986.
- ©1987 American Association for Cancer Research.