PHARMACOKINETICS OF METHOTREXATE AFTER INTRAVENOUS AND INTRAMUSCULAR INJECTION OF METHOTREXATE-BEARING NEUTRAL LIPOSOMES TO RATS

The pharmacokinetics and tissue distribution of methotrexate (MTX) wer e investigated after intravenous (i.v.) and intramuscular (i.m.) injec tion of free MTX (treatment I), MTX-bearing neutral liposomes (large u nilamellar vesicles), OLUVs (treatment II) and free MTX mixed manually with empty OLUVs (treatment III), 4mg/kg as free MTX to rats. After i .v. infusion in 1 min, the plasma concentrations of MTX (C-p), area un der the plasma concentration-time curve (AUC, 173 vs. 1110 mu g ml/min ), terminal half-life (t(1/2), 24.0 min vs. not determined), mean resi dence time (MRT, 13.0 vs. 165 min) and apparent volume of distribution at steady state (V-ss, 289 vs. 584 ml/kg) increased significantly; ho wever, total body clearance (Cl, 23.1 vs. 3.61 ml/min/kg), renal clear ance (Cl-R, 8.38 vs. 1.88 ml/min/kg) and nonrenal clearance (Cl-NR, 14 6 vs. 1 66 ml/min/kg) decreased significantly from treatment II when compared with the values from treatment I. This could be due to the fa ct that some of the MTX-bearing OLUVs were entrapped in tissues and th e others were present in plasma (increase in MRT and V-SS from treatme nt II). MTX was slowly released from the MTX-bearing OLUVs (increase i n t(1/2) from treatment II), With the present HPLC assay, the concentr ations of MTX represent the sum of the free MTX and MTX in MTX-bearing OLUVs (increase in C-p and AUC, and decrease in Cl from treatment II) . Some pharmacokinetic parameters of MTX, such as t(1/2) (24.0 vs. 58. 2 min), MRT (13.0 vs. 23.3 min) and V-SS (289 vs. 456 ml/kg) were sign ificantly different after i.v. administration of empty OLUVs (between treatments I and III); however, the differences seemed to be smaller t han those between treatments I and II. After i.m. administration, t(1/ 2) (37.2 min vs. not determined) and the total amounts of MTX excreted in urine (X(u), 319 vs. 171 mu g) were significantly different after treatments I and II. After both i.v. and i.m. administration, the amou nt of MTX remaining per gram of tissue, and/or tissue to plasma ratio (T/P) of MTX were significantly reduced in the kidney, small intestine , large intestine or stomach from treatment II when compared with thos e from treatment I. This implies that the side-effects of MTX on the k idney and gastrointestinal tract could be reduced after i.v. or i.m. a dministration of MTX-bearing OLUVs rather than free MTX. The mean enca psulation efficiency of MTX in MTX-bearing OLUVs was 3.88% and the MTX was released slowly from MTX-bearing OLUVs when incubated in phosphat e-buffered saline, rat plasma and rat liver homogenate.