title: Facilitated transport of melphalan at the rat blood-brain barrier by the large neutral amino acid carrier system.
abstract: 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 pharmacokinetics. 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 O to 16.3 mumol/ml. The permeability-surface area product was concentration dependent and decreased from 10.8 +/- 0.6 (+/- SE) X 10(-4)S-1 at 0.02 mumol/ml melphalan to 5.4 +/- 0.3 X 10(-4)S-1 at 16.3 mumol/ml. The system became saturated at a concentration in excess of 0.1 mumol/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 X 10(-4) mumol/s/g and 0.15 +/- 0.06 mumol/ml, respectively, for the saturable component of melphalan's brain uptake. The Kd of the nonsaturable component was 5.3 +/- 0.03 X 10(-4)S-1. Addition of the amino acid 1-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.
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008558:Melphalan / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000596:Amino Acids; D008558:Melphalan